Obesity

Since the last Practice Alert update on recommendations made by the US Preventive Services Task Force,¹ the Task Force has completed work on 12 topics (TABLE 1).^2-17 Five of these topics have been discussed in JFP audio recordings, and the links are provided in TABLE 1.

This latest Task Force endeavor resulted in 18 recommendations (TABLE 2), all of which reaffirm previous recommendations on these topics and expand the scope of 2. There were 2 “A” recommendations, 6 “B” recommendations, 2 “D” recommendations, and 8 “I” statements, indicating that there was insufficient evidence to assess effectiveness or harms. The willingness to make “I” statements when there is little or no evidence on the intervention being assessed distinguishes the USPSTF from other clinical guideline committees.

Screening for carotid artery stenosis

One of the “D” recommendations this past year reaffirms the prior recommendation against screening for carotid artery stenosis in asymptomatic adults—ie, those without a history of transient ischemic attack, stroke, or neurologic signs or symptoms that might be caused by carotid artery stenosis.² The screening tests the Task Force researched included carotid duplex ultrasonography (DUS), magnetic resonance angiography, and computed tomography angiography. The Task Force did not look at the value of auscultation for carotid bruits because it has been proven to be inaccurate and they do not consider it to be a useful screening tool. 

The Task Force based its “D” recommendation on a lack of evidence for any benefit in detecting asymptomatic carotid artery stenosis, and on evidence that screening can lead to harms through false-positive tests and potential complications from carotid endarterectomy and carotid artery angioplasty and stenting. In its clinical considerations, the Task Force emphasized the primary prevention of atherosclerotic disease by focusing on the following actions:

• screening for high blood pressure in adults
• encouraging tobacco smoking cessation in adults
• promoting a healthy diet and physical activity in adults with cardiovascular risk factors
• recommending aspirin use to prevent cardiovascular disease and colorectal cancer
• advising statin use for the primary prevention of cardiovascular disease in adults ages 45 to 75 years who have 1 or more risk factors (hyperlipidemia, diabetes, hypertension, smoking) and those with a 10-year risk of a cardiovascular event of 10% or greater.

This “D” recommendation differs from recommendations made by other professional organizations, some of which recommend testing with DUS for asymptomatic patients with a carotid bruit, and others that recommend DUS screening in patients with multiple risk factors for stroke and in those with known peripheral artery disease or other cardiovascular disease.^18,19

Smoking cessation in adults

Smoking tobacco is the leading preventable cause of death in the United States, causing about 480,000 deaths annually.³ Smoking during pregnancy increases the risk of complications including miscarriage, congenital anomalies, stillbirth, fetal growth restriction, preterm birth, and placental abruption.

The Task Force published recommendations earlier this year advising all clinicians to ask all adult patients about tobacco use; and, for those who smoke, to provide (or refer them to) smoking cessation behavioral therapy. The Task Force also recommends prescribing pharmacotherapy approved by the Food and Drug Administration (FDA) for smoking cessation for nonpregnant adults. (There is a lack of information to assess the harms and benefits of smoking cessation pharmacotherapy during pregnancy.)

Continue to: FDA-approved medications...

The Task Force recommends prescribing pharmacotherapy approved by the FDA for smoking cessation for nonpregnant adults.

FDA-approved medications for treating tobacco smoking dependence are nicotine replacement therapy (NRT), bupropion hydrochloride, and varenicline.³ NRT is available in transdermal patches, lozenges, gum, inhalers, and nasal sprays.

In addition, the Task Force indicates that there is insufficient evidence to assess the benefits and harms of e-cigarettes when used as a method of achieving smoking cessation: “Few randomized trials have evaluated the effectiveness of e-cigarettes to increase tobacco smoking cessation in nonpregnant adults, and no trials have evaluated e-­cigarettes for tobacco smoking cessation in pregnant persons.”⁴

Hepatitis B infection screening

The Task Force reaffirmed a previous recommendation to screen for hepatitis B virus (HBV) infection only in adults who are at high risk,⁵ rather than universal screening that it recommends for hepatitis C virus infection (HCV).⁷ (See: https://bit.ly/3tt064Q). The Task Force has a separate recommendation to screen all pregnant women for hepatitis B at the first prenatal visit.⁶

Those at high risk for hepatitis B who should be screened include individuals born in countries or regions of the world with a hepatitis B surface antigen (HBsAg) prevalence ≥ 2% and individuals born in the United States who have not received HBV vaccine and whose parents were born in regions with an HBsAg prevalence ≥ 8%.⁵ (A table listing countries with HBsAg ≥ 8%—as well as those in lower prevalence categories—is included with the recommendation.⁵)

Screening individuals at high risk for HBV infection is important because nearly two-thirds of those infected are unaware of their condition.

HBV screening should also be offered to other high-risk groups that have a prevalence of positive HBsAg ≥ 2%: those who have injected drugs in the past or are currently injecting drugs; men who have sex with men; individuals with HIV; and sex partners, needle-sharing contacts, and household contacts of people known to be HBsAg positive.⁵

Continue to: It is estimated that...

It is estimated that > 860,000 people in the United States have chronic HBV infection and that close to two-thirds of them are unaware of their infection.⁵ The screening test for HBV is highly accurate; sensitivity and specificity are both > 98%.⁵ While there is no direct evidence that screening, detecting, and treating asymptomatic HBV infection reduces morbidity and mortality, the Task Force felt that the evidence for improvement in multiple outcomes in those with HBV when treated with antiviral regimens was sufficient to support the recommendation.

Screening for bacterial vaginosis in pregnancy

While bacterial vaginosis (BV) is associated with a two-fold risk of preterm delivery, treating BV during pregnancy does not seem to reduce this risk, indicating that some other variable is involved.⁸ In addition, studies that looked at screening for, and treatment of, ­asymptomatic BV in pregnant women at high risk for preterm delivery (defined primarily as those with a previous preterm delivery) have shown inconsistent results. There is the potential for harm in treating BV in pregnancy, chiefly involving gastrointestinal upset caused by metronidazole or clindamycin.

Given that there are no benefits—and some harms—resulting from treatment, the Task Force recommends against screening for BV in non-high-risk pregnant women. A lack of sufficient information to assess any potential benefits to screening in high-risk pregnancies led the Task Force to an “I” statement on this question.⁸

Behavioral counseling on healthy diet, exercise for adults with CV risks

Cardiovascular disease (CVD) remains the number one cause of death in the United States. The major risk factors for CVD, which can be modified, are high blood pressure, hyperlipidemia, diabetes, smoking, obesity or overweight, and lack of physical activity.

The Task Force has previously recommended intensive behavioral interventions to improve nutrition and physical activity in those who are overweight/obese and in those with abnormal blood glucose levels,⁹ and has addressed smoking prevention and cessation.⁴ This new recommendation applies to those with other CVD risks such as high blood pressure and/or hyperlipidemia and those with an estimated 10-year CVD risk of ≥ 7.5%.¹⁰

Continue to: Behavioral interventions...

Behavioral interventions included in the Task Force analysis employed a median of 12 contacts and an estimated 6 hours of contact time over 6 to 18 months.¹⁰ Most interventions involved motivational interviewing and instruction on behavioral change methods. These interventions can be provided by primary care clinicians, as well as a wide range of other trained professionals. The Affordable Care Act dictates that all “A” and “B” recommendations must be provided by commercial health plans at no out-of-pocket expense for the patient.

Nutritional advice should include reductions in saturated fats, salt, and sugars and increases in fruits, vegetables, and whole grains. The Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet are often recommended.¹⁰ Physical activity counseling should advocate for 90 to 180 minutes per week of moderate to vigorous activity.

This new recommendation, along with the previous ones pertaining to behavioral interventions for lifestyle changes, make it clear that intensive interventions are needed to achieve meaningful change. Simple advice from a clinician will have little to no effect.

Task Force reviews evidence on HTN, smoking cessation in young people

In 2020 the Task Force completed reviews of evidence relevant to screening for high blood pressure¹¹ and intervening for tobacco prevention and cessation in children and adolescents.¹² The Task Force concluded that the evidence is insufficient to make a judgment on screening for high blood pressure and for providing smoking cessation interventions. It did, however, reaffirm a previous recommendation to provide interventions to children and adolescents to prevent tobacco and e-cigarette use.

Screening for asymptomatic carotid artery stenosis is discouraged due to a lack of evidence for benefit in detection, and on evidence that false-positives lead to harm from procedures such as endarterectomy.

The 2 “I” statements are in disagreement with recommendations of other professional organizations. The American Academy of Pediatrics (AAP) and the American Heart Association recommend routine screening for high blood pressure starting at age 3 years. And the AAP recommends screening teenagers for tobacco use and offering tobacco dependence treatment, referral, or both (including pharmacotherapy) when indicated. E-cigarettes are not recommended as a treatment for tobacco dependence.²⁰

Continue to: The difference between...

The difference between the methods used by the Task Force and other guideline-­producing organizations becomes apparent when it comes to recommendations pertaining to children and adolescents, for whom long-term outcome-oriented studies on prevention issues are rare. The Task Force is unwilling to make recommendations when evidence does not exist. The AAP often makes recommendations based on expert opinion consensus in such situations. One notable part of each Task Force recommendation statement is a discussion of what other organizations recommend on the same topic so that these differences can be openly described.

Better Task Force funding could expand topic coverage

It is worth revisiting 2 issues that were pointed out in last year’s USPSTF summary in this column.¹ First, the Task Force methods are robust and evidence based, and recommendations therefore are rarely changed once they are made at an “A”, “B”, or “D” level. Second, Task Force resources are finite, and thus, the group is currently unable to update previous recommendations with greater frequency or to consider many new topics. In the past 2 years, the Task Force has developed recommendations on only 2 completely new topics. Hopefully, its budget can be expanded so that new topics can be added in the future.

Since the last Practice Alert update on recommendations made by the US Preventive Services Task Force,¹ the Task Force has completed work on 12 topics (TABLE 1).^2-17 Five of these topics have been discussed in JFP audio recordings, and the links are provided in TABLE 1.

This latest Task Force endeavor resulted in 18 recommendations (TABLE 2), all of which reaffirm previous recommendations on these topics and expand the scope of 2. There were 2 “A” recommendations, 6 “B” recommendations, 2 “D” recommendations, and 8 “I” statements, indicating that there was insufficient evidence to assess effectiveness or harms. The willingness to make “I” statements when there is little or no evidence on the intervention being assessed distinguishes the USPSTF from other clinical guideline committees.

Screening for carotid artery stenosis

One of the “D” recommendations this past year reaffirms the prior recommendation against screening for carotid artery stenosis in asymptomatic adults—ie, those without a history of transient ischemic attack, stroke, or neurologic signs or symptoms that might be caused by carotid artery stenosis.² The screening tests the Task Force researched included carotid duplex ultrasonography (DUS), magnetic resonance angiography, and computed tomography angiography. The Task Force did not look at the value of auscultation for carotid bruits because it has been proven to be inaccurate and they do not consider it to be a useful screening tool. 

The Task Force based its “D” recommendation on a lack of evidence for any benefit in detecting asymptomatic carotid artery stenosis, and on evidence that screening can lead to harms through false-positive tests and potential complications from carotid endarterectomy and carotid artery angioplasty and stenting. In its clinical considerations, the Task Force emphasized the primary prevention of atherosclerotic disease by focusing on the following actions:

• screening for high blood pressure in adults
• encouraging tobacco smoking cessation in adults
• promoting a healthy diet and physical activity in adults with cardiovascular risk factors
• recommending aspirin use to prevent cardiovascular disease and colorectal cancer
• advising statin use for the primary prevention of cardiovascular disease in adults ages 45 to 75 years who have 1 or more risk factors (hyperlipidemia, diabetes, hypertension, smoking) and those with a 10-year risk of a cardiovascular event of 10% or greater.

This “D” recommendation differs from recommendations made by other professional organizations, some of which recommend testing with DUS for asymptomatic patients with a carotid bruit, and others that recommend DUS screening in patients with multiple risk factors for stroke and in those with known peripheral artery disease or other cardiovascular disease.^18,19

Smoking cessation in adults

Smoking tobacco is the leading preventable cause of death in the United States, causing about 480,000 deaths annually.³ Smoking during pregnancy increases the risk of complications including miscarriage, congenital anomalies, stillbirth, fetal growth restriction, preterm birth, and placental abruption.

The Task Force published recommendations earlier this year advising all clinicians to ask all adult patients about tobacco use; and, for those who smoke, to provide (or refer them to) smoking cessation behavioral therapy. The Task Force also recommends prescribing pharmacotherapy approved by the Food and Drug Administration (FDA) for smoking cessation for nonpregnant adults. (There is a lack of information to assess the harms and benefits of smoking cessation pharmacotherapy during pregnancy.)

Continue to: FDA-approved medications...

The Task Force recommends prescribing pharmacotherapy approved by the FDA for smoking cessation for nonpregnant adults.

FDA-approved medications for treating tobacco smoking dependence are nicotine replacement therapy (NRT), bupropion hydrochloride, and varenicline.³ NRT is available in transdermal patches, lozenges, gum, inhalers, and nasal sprays.

In addition, the Task Force indicates that there is insufficient evidence to assess the benefits and harms of e-cigarettes when used as a method of achieving smoking cessation: “Few randomized trials have evaluated the effectiveness of e-cigarettes to increase tobacco smoking cessation in nonpregnant adults, and no trials have evaluated e-­cigarettes for tobacco smoking cessation in pregnant persons.”⁴

Hepatitis B infection screening

The Task Force reaffirmed a previous recommendation to screen for hepatitis B virus (HBV) infection only in adults who are at high risk,⁵ rather than universal screening that it recommends for hepatitis C virus infection (HCV).⁷ (See: https://bit.ly/3tt064Q). The Task Force has a separate recommendation to screen all pregnant women for hepatitis B at the first prenatal visit.⁶

Those at high risk for hepatitis B who should be screened include individuals born in countries or regions of the world with a hepatitis B surface antigen (HBsAg) prevalence ≥ 2% and individuals born in the United States who have not received HBV vaccine and whose parents were born in regions with an HBsAg prevalence ≥ 8%.⁵ (A table listing countries with HBsAg ≥ 8%—as well as those in lower prevalence categories—is included with the recommendation.⁵)

Screening individuals at high risk for HBV infection is important because nearly two-thirds of those infected are unaware of their condition.

HBV screening should also be offered to other high-risk groups that have a prevalence of positive HBsAg ≥ 2%: those who have injected drugs in the past or are currently injecting drugs; men who have sex with men; individuals with HIV; and sex partners, needle-sharing contacts, and household contacts of people known to be HBsAg positive.⁵

Continue to: It is estimated that...

It is estimated that > 860,000 people in the United States have chronic HBV infection and that close to two-thirds of them are unaware of their infection.⁵ The screening test for HBV is highly accurate; sensitivity and specificity are both > 98%.⁵ While there is no direct evidence that screening, detecting, and treating asymptomatic HBV infection reduces morbidity and mortality, the Task Force felt that the evidence for improvement in multiple outcomes in those with HBV when treated with antiviral regimens was sufficient to support the recommendation.

Screening for bacterial vaginosis in pregnancy

While bacterial vaginosis (BV) is associated with a two-fold risk of preterm delivery, treating BV during pregnancy does not seem to reduce this risk, indicating that some other variable is involved.⁸ In addition, studies that looked at screening for, and treatment of, ­asymptomatic BV in pregnant women at high risk for preterm delivery (defined primarily as those with a previous preterm delivery) have shown inconsistent results. There is the potential for harm in treating BV in pregnancy, chiefly involving gastrointestinal upset caused by metronidazole or clindamycin.

Given that there are no benefits—and some harms—resulting from treatment, the Task Force recommends against screening for BV in non-high-risk pregnant women. A lack of sufficient information to assess any potential benefits to screening in high-risk pregnancies led the Task Force to an “I” statement on this question.⁸

Behavioral counseling on healthy diet, exercise for adults with CV risks

Cardiovascular disease (CVD) remains the number one cause of death in the United States. The major risk factors for CVD, which can be modified, are high blood pressure, hyperlipidemia, diabetes, smoking, obesity or overweight, and lack of physical activity.

The Task Force has previously recommended intensive behavioral interventions to improve nutrition and physical activity in those who are overweight/obese and in those with abnormal blood glucose levels,⁹ and has addressed smoking prevention and cessation.⁴ This new recommendation applies to those with other CVD risks such as high blood pressure and/or hyperlipidemia and those with an estimated 10-year CVD risk of ≥ 7.5%.¹⁰

Continue to: Behavioral interventions...

Behavioral interventions included in the Task Force analysis employed a median of 12 contacts and an estimated 6 hours of contact time over 6 to 18 months.¹⁰ Most interventions involved motivational interviewing and instruction on behavioral change methods. These interventions can be provided by primary care clinicians, as well as a wide range of other trained professionals. The Affordable Care Act dictates that all “A” and “B” recommendations must be provided by commercial health plans at no out-of-pocket expense for the patient.

Nutritional advice should include reductions in saturated fats, salt, and sugars and increases in fruits, vegetables, and whole grains. The Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet are often recommended.¹⁰ Physical activity counseling should advocate for 90 to 180 minutes per week of moderate to vigorous activity.

This new recommendation, along with the previous ones pertaining to behavioral interventions for lifestyle changes, make it clear that intensive interventions are needed to achieve meaningful change. Simple advice from a clinician will have little to no effect.

Task Force reviews evidence on HTN, smoking cessation in young people

In 2020 the Task Force completed reviews of evidence relevant to screening for high blood pressure¹¹ and intervening for tobacco prevention and cessation in children and adolescents.¹² The Task Force concluded that the evidence is insufficient to make a judgment on screening for high blood pressure and for providing smoking cessation interventions. It did, however, reaffirm a previous recommendation to provide interventions to children and adolescents to prevent tobacco and e-cigarette use.

Screening for asymptomatic carotid artery stenosis is discouraged due to a lack of evidence for benefit in detection, and on evidence that false-positives lead to harm from procedures such as endarterectomy.

The 2 “I” statements are in disagreement with recommendations of other professional organizations. The American Academy of Pediatrics (AAP) and the American Heart Association recommend routine screening for high blood pressure starting at age 3 years. And the AAP recommends screening teenagers for tobacco use and offering tobacco dependence treatment, referral, or both (including pharmacotherapy) when indicated. E-cigarettes are not recommended as a treatment for tobacco dependence.²⁰

Continue to: The difference between...

The difference between the methods used by the Task Force and other guideline-­producing organizations becomes apparent when it comes to recommendations pertaining to children and adolescents, for whom long-term outcome-oriented studies on prevention issues are rare. The Task Force is unwilling to make recommendations when evidence does not exist. The AAP often makes recommendations based on expert opinion consensus in such situations. One notable part of each Task Force recommendation statement is a discussion of what other organizations recommend on the same topic so that these differences can be openly described.

Better Task Force funding could expand topic coverage

It is worth revisiting 2 issues that were pointed out in last year’s USPSTF summary in this column.¹ First, the Task Force methods are robust and evidence based, and recommendations therefore are rarely changed once they are made at an “A”, “B”, or “D” level. Second, Task Force resources are finite, and thus, the group is currently unable to update previous recommendations with greater frequency or to consider many new topics. In the past 2 years, the Task Force has developed recommendations on only 2 completely new topics. Hopefully, its budget can be expanded so that new topics can be added in the future.

Since the last Practice Alert update on recommendations made by the US Preventive Services Task Force,¹ the Task Force has completed work on 12 topics (TABLE 1).^2-17 Five of these topics have been discussed in JFP audio recordings, and the links are provided in TABLE 1.

This latest Task Force endeavor resulted in 18 recommendations (TABLE 2), all of which reaffirm previous recommendations on these topics and expand the scope of 2. There were 2 “A” recommendations, 6 “B” recommendations, 2 “D” recommendations, and 8 “I” statements, indicating that there was insufficient evidence to assess effectiveness or harms. The willingness to make “I” statements when there is little or no evidence on the intervention being assessed distinguishes the USPSTF from other clinical guideline committees.

Screening for carotid artery stenosis

One of the “D” recommendations this past year reaffirms the prior recommendation against screening for carotid artery stenosis in asymptomatic adults—ie, those without a history of transient ischemic attack, stroke, or neurologic signs or symptoms that might be caused by carotid artery stenosis.² The screening tests the Task Force researched included carotid duplex ultrasonography (DUS), magnetic resonance angiography, and computed tomography angiography. The Task Force did not look at the value of auscultation for carotid bruits because it has been proven to be inaccurate and they do not consider it to be a useful screening tool. 

The Task Force based its “D” recommendation on a lack of evidence for any benefit in detecting asymptomatic carotid artery stenosis, and on evidence that screening can lead to harms through false-positive tests and potential complications from carotid endarterectomy and carotid artery angioplasty and stenting. In its clinical considerations, the Task Force emphasized the primary prevention of atherosclerotic disease by focusing on the following actions:

• screening for high blood pressure in adults
• encouraging tobacco smoking cessation in adults
• promoting a healthy diet and physical activity in adults with cardiovascular risk factors
• recommending aspirin use to prevent cardiovascular disease and colorectal cancer
• advising statin use for the primary prevention of cardiovascular disease in adults ages 45 to 75 years who have 1 or more risk factors (hyperlipidemia, diabetes, hypertension, smoking) and those with a 10-year risk of a cardiovascular event of 10% or greater.

This “D” recommendation differs from recommendations made by other professional organizations, some of which recommend testing with DUS for asymptomatic patients with a carotid bruit, and others that recommend DUS screening in patients with multiple risk factors for stroke and in those with known peripheral artery disease or other cardiovascular disease.^18,19

Smoking cessation in adults

Smoking tobacco is the leading preventable cause of death in the United States, causing about 480,000 deaths annually.³ Smoking during pregnancy increases the risk of complications including miscarriage, congenital anomalies, stillbirth, fetal growth restriction, preterm birth, and placental abruption.

The Task Force published recommendations earlier this year advising all clinicians to ask all adult patients about tobacco use; and, for those who smoke, to provide (or refer them to) smoking cessation behavioral therapy. The Task Force also recommends prescribing pharmacotherapy approved by the Food and Drug Administration (FDA) for smoking cessation for nonpregnant adults. (There is a lack of information to assess the harms and benefits of smoking cessation pharmacotherapy during pregnancy.)

Continue to: FDA-approved medications...

The Task Force recommends prescribing pharmacotherapy approved by the FDA for smoking cessation for nonpregnant adults.

FDA-approved medications for treating tobacco smoking dependence are nicotine replacement therapy (NRT), bupropion hydrochloride, and varenicline.³ NRT is available in transdermal patches, lozenges, gum, inhalers, and nasal sprays.

In addition, the Task Force indicates that there is insufficient evidence to assess the benefits and harms of e-cigarettes when used as a method of achieving smoking cessation: “Few randomized trials have evaluated the effectiveness of e-cigarettes to increase tobacco smoking cessation in nonpregnant adults, and no trials have evaluated e-­cigarettes for tobacco smoking cessation in pregnant persons.”⁴

Hepatitis B infection screening

The Task Force reaffirmed a previous recommendation to screen for hepatitis B virus (HBV) infection only in adults who are at high risk,⁵ rather than universal screening that it recommends for hepatitis C virus infection (HCV).⁷ (See: https://bit.ly/3tt064Q). The Task Force has a separate recommendation to screen all pregnant women for hepatitis B at the first prenatal visit.⁶

Those at high risk for hepatitis B who should be screened include individuals born in countries or regions of the world with a hepatitis B surface antigen (HBsAg) prevalence ≥ 2% and individuals born in the United States who have not received HBV vaccine and whose parents were born in regions with an HBsAg prevalence ≥ 8%.⁵ (A table listing countries with HBsAg ≥ 8%—as well as those in lower prevalence categories—is included with the recommendation.⁵)

Screening individuals at high risk for HBV infection is important because nearly two-thirds of those infected are unaware of their condition.

HBV screening should also be offered to other high-risk groups that have a prevalence of positive HBsAg ≥ 2%: those who have injected drugs in the past or are currently injecting drugs; men who have sex with men; individuals with HIV; and sex partners, needle-sharing contacts, and household contacts of people known to be HBsAg positive.⁵

Continue to: It is estimated that...

It is estimated that > 860,000 people in the United States have chronic HBV infection and that close to two-thirds of them are unaware of their infection.⁵ The screening test for HBV is highly accurate; sensitivity and specificity are both > 98%.⁵ While there is no direct evidence that screening, detecting, and treating asymptomatic HBV infection reduces morbidity and mortality, the Task Force felt that the evidence for improvement in multiple outcomes in those with HBV when treated with antiviral regimens was sufficient to support the recommendation.

Screening for bacterial vaginosis in pregnancy

While bacterial vaginosis (BV) is associated with a two-fold risk of preterm delivery, treating BV during pregnancy does not seem to reduce this risk, indicating that some other variable is involved.⁸ In addition, studies that looked at screening for, and treatment of, ­asymptomatic BV in pregnant women at high risk for preterm delivery (defined primarily as those with a previous preterm delivery) have shown inconsistent results. There is the potential for harm in treating BV in pregnancy, chiefly involving gastrointestinal upset caused by metronidazole or clindamycin.

Given that there are no benefits—and some harms—resulting from treatment, the Task Force recommends against screening for BV in non-high-risk pregnant women. A lack of sufficient information to assess any potential benefits to screening in high-risk pregnancies led the Task Force to an “I” statement on this question.⁸

Behavioral counseling on healthy diet, exercise for adults with CV risks

Cardiovascular disease (CVD) remains the number one cause of death in the United States. The major risk factors for CVD, which can be modified, are high blood pressure, hyperlipidemia, diabetes, smoking, obesity or overweight, and lack of physical activity.

The Task Force has previously recommended intensive behavioral interventions to improve nutrition and physical activity in those who are overweight/obese and in those with abnormal blood glucose levels,⁹ and has addressed smoking prevention and cessation.⁴ This new recommendation applies to those with other CVD risks such as high blood pressure and/or hyperlipidemia and those with an estimated 10-year CVD risk of ≥ 7.5%.¹⁰

Continue to: Behavioral interventions...

Behavioral interventions included in the Task Force analysis employed a median of 12 contacts and an estimated 6 hours of contact time over 6 to 18 months.¹⁰ Most interventions involved motivational interviewing and instruction on behavioral change methods. These interventions can be provided by primary care clinicians, as well as a wide range of other trained professionals. The Affordable Care Act dictates that all “A” and “B” recommendations must be provided by commercial health plans at no out-of-pocket expense for the patient.

Nutritional advice should include reductions in saturated fats, salt, and sugars and increases in fruits, vegetables, and whole grains. The Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet are often recommended.¹⁰ Physical activity counseling should advocate for 90 to 180 minutes per week of moderate to vigorous activity.

This new recommendation, along with the previous ones pertaining to behavioral interventions for lifestyle changes, make it clear that intensive interventions are needed to achieve meaningful change. Simple advice from a clinician will have little to no effect.

Task Force reviews evidence on HTN, smoking cessation in young people

In 2020 the Task Force completed reviews of evidence relevant to screening for high blood pressure¹¹ and intervening for tobacco prevention and cessation in children and adolescents.¹² The Task Force concluded that the evidence is insufficient to make a judgment on screening for high blood pressure and for providing smoking cessation interventions. It did, however, reaffirm a previous recommendation to provide interventions to children and adolescents to prevent tobacco and e-cigarette use.

Screening for asymptomatic carotid artery stenosis is discouraged due to a lack of evidence for benefit in detection, and on evidence that false-positives lead to harm from procedures such as endarterectomy.

The 2 “I” statements are in disagreement with recommendations of other professional organizations. The American Academy of Pediatrics (AAP) and the American Heart Association recommend routine screening for high blood pressure starting at age 3 years. And the AAP recommends screening teenagers for tobacco use and offering tobacco dependence treatment, referral, or both (including pharmacotherapy) when indicated. E-cigarettes are not recommended as a treatment for tobacco dependence.²⁰

Continue to: The difference between...

The difference between the methods used by the Task Force and other guideline-­producing organizations becomes apparent when it comes to recommendations pertaining to children and adolescents, for whom long-term outcome-oriented studies on prevention issues are rare. The Task Force is unwilling to make recommendations when evidence does not exist. The AAP often makes recommendations based on expert opinion consensus in such situations. One notable part of each Task Force recommendation statement is a discussion of what other organizations recommend on the same topic so that these differences can be openly described.

Better Task Force funding could expand topic coverage

It is worth revisiting 2 issues that were pointed out in last year’s USPSTF summary in this column.¹ First, the Task Force methods are robust and evidence based, and recommendations therefore are rarely changed once they are made at an “A”, “B”, or “D” level. Second, Task Force resources are finite, and thus, the group is currently unable to update previous recommendations with greater frequency or to consider many new topics. In the past 2 years, the Task Force has developed recommendations on only 2 completely new topics. Hopefully, its budget can be expanded so that new topics can be added in the future.

Approximately 60 million people in the United States run for exercise at least once a calendar year, with approximately 11 million of them running > 100 days a year.^1,2 Running is an affordable, convenient, and efficient form of exercise, whose benefits include a decrease in the risk of all-cause early mortality, cancer, and diabetes; an improved lipid profile; and better mental health.³

However, running is also the cause of a significant percentage of exercise-associated injuries: More than 60% of runners report overuse injury annually.⁴ Given the high incidence of running-related injury, an important component of primary care is accurately diagnosing and managing such injuries and counseling patients about how to prevent them.

This article reviews risk factors for running-related injury and summarizes evidence-based recommendations for prevention.

CASE

During a health maintenance examination, Clara K, a 47-year-old woman who is obese (body mass index [BMI], 34) and has bilateral knee osteoarthritis (OA), inquires about establishing a weight-loss strategy. Ms. K is interested in starting an exercise regimen involving running but is worried about provoking a flare of OA pain.

Risk factors for running injuries

Several risk factors—some modifiable, others nonmodifiable—are associated with running-related injury (TABLE 1^4-16). In addition, research suggests that other variables once thought to be risk factors, such as running surface and the Q-angle (described later), are not associated with running-related injury.

Modifiable risk factors

Changes in a training regimen or type of training. Many runners escalate training regimens as their fitness improves. Increasing mileage and changing the type of training (such as introducing hills or interval training) are independent risk factors for sustaining injury.⁵

Running is an affordable, convenient, and efficient form of exercise; however, more than 60% of runners report overuse injury annually.

The traditional recommendation has been for a runner to slowly increase or modify training with a 10% weekly increase in mileage or intensity.¹⁷ However, a randomized controlled trial failed to show a lower incidence of injury among amateur runners who adopted a graded exercise program.¹⁸ Regardless: It is still prudent to recommend a gradual increase in activity, such as taking ≥ 1 day off between running workouts or starting with a walking or jogging program, especially when there is a history of injury.¹⁹

Continue to: Excessive mileage

Excessive mileage. Many runners aspire to complete high-mileage runs. There is low-quality evidence demonstrating that high-mileage running, especially > 40 miles per week, is associated with increased risk of running-related injury.⁵ Injuries that occur with higher mileage are more often those of the hip and hamstring.⁵ A study noted that running ≤ 25 miles a week was protective against calf injury.⁶

Overall, there is little evidence to show that high-mileage running is associated with increased risk of running-related injury. However, this is still a risk factor that you should address with patients who have a running program—especially novices and those who ramp up mileage quickly.

Type of surface. Access to running surfaces—concrete, pavement, trails, treadmills, and athletic tracks—varies by time of day and season. Softer surfaces include treadmill, tracks, and trails; harder surfaces include asphalt and concrete.

There are limited data linking running surface with risk of injury.⁷ A study did not find an association between peak impact force based on running surface⁸; the authors hypothesized that runners compensate for a harder surface by making kinematic adjustments to minimize impact. With no strong evidence to link running-related injury to a particular running surface, patients should not be restricted to a softer running surface unless they notice a difference in comfort, because it is likely that they can compensate for a harder surface by adapting their gait.

Patients can therefore be counseled to run locally on sidewalks and neighborhood streets—if safe to do so—instead of obtaining a gym membership or driving to run on a trail. Such reassurance can increase a patient’s access to running and reduce barriers to exercise.

Continue to: BMI

BMI. Elevated BMI increases joint contact forces, which might increase risk of pain and injury.²⁰ Results of studies investigating the link between BMI and running injury are mixed; some report that, in regard to bone stress injury, overweight BMI (> 25) is a risk factor for male runners and underweight BMI (< 18.5) is a risk factor for female runners.^4,6 An observational study concluded that, among half-marathon and marathon runners, there was no significant increase in race-related injury, based on BMI.⁹ However, another study showed a higher rate of running-related injury in novice runners who had a higher BMI.¹⁰ A prospective cohort study found that runners with a higher BMI reported increased knee stiffness, which can place a runner at higher risk of overuse injury.⁴

Although these results conflict, there is consistency in the finding that obese novice runners are likely at increased risk of running-related injury; it is reasonable, therefore, for you to discuss strategies to reduce the risk of other modifiable factors, especially among obese novice runners. Patients with a higher BMI should not be discouraged from running, because exercise in combination with healthy eating habits is essential to decrease the myriad adverse health outcomes associated with obesity.

Female runners with a lower BMI, especially in the presence of other components of the female athlete triad (inadequate nutrition, amenorrhea, and low bone density), should be counseled about their increased risk of bone stress injury.²¹ Notably, a study of female US Navy recruits randomized to receive a trial of dietary supplementation of vitamin D plus calcium, or placebo, showed a 21% lower incidence of bone stress injury in the active-treatment group.²² To mitigate risk of injury associated with low BMI and the female athlete triad, therefore, a multidisciplinary approach of nutrition intervention, dietary optimization of vitamin D and calcium, and, possibly, activity modification should be implemented when appropriate.

Running gait. A study using 2-dimensional gait analysis to visualize biomechanical running patterns in injured and noninjured runners found that, in regard to mechanical variables, running-related injury was most strongly associated with contralateral pelvic drop.²³ Gait retraining can be employed to help decrease contralateral pelvic drop.²⁴ In addition, pelvic drop is often a result of weak gluteal muscles, and can be improved by doing strengthening exercises at home or with physical therapy.

Longer stride is also associated with running-related injury.²⁵ A study showed improvement in patellofemoral pain by having runners increase stride rate by 10%, which reduces stride length to a significant degree.^25,26 These improvements were maintained at 1-month and 3-month follow-up, and required only 1 gait retraining session.

Continue to: Get analysis is not feasible...

Gait analysis is not feasible in most primary care clinics. Instead, patients who run and (1) in whom pain persists despite more traditional treatments and (2) who have had recurring injury should be referred to a gait lab for analysis, usually by a physical therapist.

Nonmodifiable risk factors

Arch height. A high arch (pes cavus) is associated with increased risk of running-related injury, including bone stress injury, Achilles tendinopathy, plantar fasciitis, and patellofemoral pain syndrome.⁵ The mechanism of injury is thought to be increased forefoot loading forces.¹

A review article showed that patients with pes cavus have reduced pain when using an orthosis, although there is no associated decrease in the risk of injury.⁵ To the contrary, a prospective study concluded that arch height was unrelated to increased risk of running-related injury.⁷

A study showed improvement in patellofemoral pain by having runners increase stride rate by 10%, which reduces stride length to a significant degree.

Evidence regarding flat feet (pes planus) and risk of injury is also mixed. Some studies show that pes planus is not associated with increased risk of injury in athletes.¹² A cross-sectional study in older patients showed those with pes planus morphology had a higher rate of knee pain and wearing away of medial compartment cartilage.¹³ Because this study comprised only older adults, it is not generalizable to runners—nor can conclusions be drawn about causation, given the cross-sectional nature of the study.

Although a foot orthosis can correct mechanical differences caused by pes planus morphology, there is not enough evidence to conclude that correction results in a lower rate of injury. In sum, data are mixed with regard to arch height as a risk factor for running-related injury.

Continue to: Patients with...

Patients with pes planus or pes cavus should not be discouraged from running, however. If they experience pain with running, they might benefit from a trial of arch support inserts; or consider referral to an orthotist for evaluation for a custom orthosis.

Sex. Based on a prospective cohort study, female runners have a slightly higher rate of running injury than male counterparts.⁴ Similarly, a study showed that female military members generally had a higher incidence of stress fractures than male military members—specifically, femoral shaft and neck stress fractures.¹⁴ Runners who fall in the spectrum of the female athlete triad, as described earlier, are particularly vulnerable to bone stress injury. It is reasonable, therefore, to review risk factors for injury with female runners (as it is with all runners), especially those who have sustained a prior running-related injury.

Increased Q-angle (an obsolete risk factor). The Q-angle is approximated by drawing a line from the anterior superior iliac spine to the patella and a second line from the patella to the tibial tubercle. In males, a normal Q-angle is 14°; in females, 17° (SD = 4.5°). The Q-angle can be obtained by goniometric or radiographic measurement.

An increased Q-angle had been considered an intrinsic risk factor for running injury but has not been shown to be associated with increased risk of running-related injury or patellofemoral pain syndrome.^27,28 Because the Q-angle is not a clinically relevant tool in assessing risk of injury, do not routinely measure it or include it in risk-factor counseling.

OA. Based on a systematic review of observational studies, data are inconclusive with regard to whether running contributes to, or is protective against, knee OA.¹⁵ In a large cohort study, running (1) was protective against development of hip OA and (2) decreased the risk of requiring hip replacement.²⁹ This finding was supported by animal-model research that concluded that it is inactivity that results in thinning of articular cartilage.²⁹ In addition, a systematic review of randomized controlled trials concluded that knee joint-loading exercises are not harmful to articular cartilage (this is low-quality evidence, however).¹⁶

Continue to: Given that there...

Given that there are no high-quality studies suggesting that running contributes to or exacerbates OA, patients with OA can be counseled to start or continue running as tolerated because the health benefit of running likely outweighs risk. Patients with pre-existing moderate-to-severe OA might report knee and hip pain that is already exacerbated by certain activities; if a high-impact activity, such as running, makes that pain worse, exercise counseling that you provide can be tailored to include lower-impact alternatives, such as swimming, cycling, or an elliptical workout.

CASE

In response to Ms. K’s interest in beginning an exercise regimen that includes running, you perform a complete routine pre-participation evaluation and appropriate cardiac screening. You discuss risk factors for running injury, focusing on modifiable risk factors.

High-mileage running, especially > 40 miles per week, is associated with increased risk of injury, most often of the hip and hamstring.

Ms. K is perimenopausal but reports a history of regular menstrual cycles. She eats a relatively well-balanced diet. You advise that her BMI should not restrict her from incorporating running into her fitness regimen. Also, you reassure her that she should not restrict running based on a diagnosis of OA; instead, you advise her to monitor her symptoms and reconsider her program if running makes her knee pain worse.

At this point, Ms. K is ready to run. She tells you that, based on your guidance, she feels more comfortable and safe starting a running program.

Preventing injury

After reviewing risk factors for running-­related injury with patients, encourage other evidence-based methods of reducing that risk.

Continue to: Shoes

 

 

Shoes

The running shoe industry offers a variety of running shoes, from minimalist shoes to cushioned stability shoes that vary based on the amount of cushioning, level of motion control, and amount of heel-to-toe drop. With so many options, new runners might wonder which shoes can reduce their risk of injury and how they should select a pair.

Stability. A characteristic of running shoes promoted by the industry is their stability: ie, their motion control. Stability shoes are marketed to runners who overpronate and therefore limit motion to prevent overpronation. The benefit of stability shoes, or stability insoles, is unclear.³⁰ A randomized controlled trial showed that, in runners who overpronate, motion-control shoes reduced their risk of injury.³¹ However, another study assessed whether shoes that had been “prescribed” based on foot morphology and stride reduced the risk of injury (compared to neutral, cushioned shoes) and found no change in the incidence of soft-tissue injury.³² Given no strong evidence to suggest otherwise, runners can be advised to buy shoes based on comfort rather than on foot morphology or running stride.

Heel-to-toe drop. Another component of shoe variability is heel-to-toe drop (the height difference between heel and forefoot). A study suggests that moderate-to-high (8-12 mm) heel-to-toe drop is associated with a reduced risk of running injury.³³ Barefoot running shoes, which, typically, have no heel-to-toe drop, are associated with increased risk of injury—specifically, foot stress fracture (especially in runners who are even moderately overweight).^34,35

Shoe age and shoe wear can be modified to reduce injury. There is evidence that running shoes lose approximately 50% of cushioning after 300 to 500 miles of use.³⁶ Another study found that rotating running shoes—ideally, different types or brands—can lead to fewer running-related injuries.³⁷

In general, patients can be counseled to use shoes that feel comfortable, as long as they replace them regularly (TABLE 2). Runners can also consider alternating pairs of different running shoes between runs. Overweight runners should avoid minimally cushioned and low heel-to-toe drop running shoes.

Continue to: Cross-training

 

 

Cross-training

Cross-training exercises for runners include cycling, an elliptical workout, swimming, and weightlifting. Incorporating cross-­training can be protective against running injury because cross-training requires different movement patterns, prevents overuse, and equalizes muscle imbalances that occur with running.⁷ In addition, replacing running with a cross-training activity can decrease weekly running time and mileage, which can further reduce risk of running-related injury.⁷ Runners—especially higher-mileage runners—should be encouraged to incorporate cross-training into their workout regimen to decrease their risk of injury.

There is no reason to counsel runners to run on a softer running surface, unless they find that doing so is more comfortable.

Stretching. The authors of a Cochrane review concluded that there is no significant reduction in injury associated with hamstring or gastrocnemius stretching.³² A small randomized, controlled, crossover study concluded that participants subjectively felt their performance was better when warm-ups included stretching.³⁸ This perceived improvement in performance was similar between groups who completed dynamic or static stretching. However, no difference was noted in flexibility or objective performance between groups who stretched or did not stretch before activity.

Although there is no supporting evidence that stretching reduces the risk of injury, stretching is a low-risk intervention. Because stretching might provide subjective benefit to runners, you need not discourage patients from including this activity in their running program.

CORRESPONDENCE
Kartik Sidhar, MD, 15370 Huff Way, Brookfield, WI, 53005; kartiksidhar@gmail.com

Approximately 60 million people in the United States run for exercise at least once a calendar year, with approximately 11 million of them running > 100 days a year.^1,2 Running is an affordable, convenient, and efficient form of exercise, whose benefits include a decrease in the risk of all-cause early mortality, cancer, and diabetes; an improved lipid profile; and better mental health.³

However, running is also the cause of a significant percentage of exercise-associated injuries: More than 60% of runners report overuse injury annually.⁴ Given the high incidence of running-related injury, an important component of primary care is accurately diagnosing and managing such injuries and counseling patients about how to prevent them.

This article reviews risk factors for running-related injury and summarizes evidence-based recommendations for prevention.

CASE

During a health maintenance examination, Clara K, a 47-year-old woman who is obese (body mass index [BMI], 34) and has bilateral knee osteoarthritis (OA), inquires about establishing a weight-loss strategy. Ms. K is interested in starting an exercise regimen involving running but is worried about provoking a flare of OA pain.

Risk factors for running injuries

Several risk factors—some modifiable, others nonmodifiable—are associated with running-related injury (TABLE 1^4-16). In addition, research suggests that other variables once thought to be risk factors, such as running surface and the Q-angle (described later), are not associated with running-related injury.

Modifiable risk factors

Changes in a training regimen or type of training. Many runners escalate training regimens as their fitness improves. Increasing mileage and changing the type of training (such as introducing hills or interval training) are independent risk factors for sustaining injury.⁵

Running is an affordable, convenient, and efficient form of exercise; however, more than 60% of runners report overuse injury annually.

The traditional recommendation has been for a runner to slowly increase or modify training with a 10% weekly increase in mileage or intensity.¹⁷ However, a randomized controlled trial failed to show a lower incidence of injury among amateur runners who adopted a graded exercise program.¹⁸ Regardless: It is still prudent to recommend a gradual increase in activity, such as taking ≥ 1 day off between running workouts or starting with a walking or jogging program, especially when there is a history of injury.¹⁹

Continue to: Excessive mileage

Excessive mileage. Many runners aspire to complete high-mileage runs. There is low-quality evidence demonstrating that high-mileage running, especially > 40 miles per week, is associated with increased risk of running-related injury.⁵ Injuries that occur with higher mileage are more often those of the hip and hamstring.⁵ A study noted that running ≤ 25 miles a week was protective against calf injury.⁶

Overall, there is little evidence to show that high-mileage running is associated with increased risk of running-related injury. However, this is still a risk factor that you should address with patients who have a running program—especially novices and those who ramp up mileage quickly.

Type of surface. Access to running surfaces—concrete, pavement, trails, treadmills, and athletic tracks—varies by time of day and season. Softer surfaces include treadmill, tracks, and trails; harder surfaces include asphalt and concrete.

There are limited data linking running surface with risk of injury.⁷ A study did not find an association between peak impact force based on running surface⁸; the authors hypothesized that runners compensate for a harder surface by making kinematic adjustments to minimize impact. With no strong evidence to link running-related injury to a particular running surface, patients should not be restricted to a softer running surface unless they notice a difference in comfort, because it is likely that they can compensate for a harder surface by adapting their gait.

Patients can therefore be counseled to run locally on sidewalks and neighborhood streets—if safe to do so—instead of obtaining a gym membership or driving to run on a trail. Such reassurance can increase a patient’s access to running and reduce barriers to exercise.

Continue to: BMI

BMI. Elevated BMI increases joint contact forces, which might increase risk of pain and injury.²⁰ Results of studies investigating the link between BMI and running injury are mixed; some report that, in regard to bone stress injury, overweight BMI (> 25) is a risk factor for male runners and underweight BMI (< 18.5) is a risk factor for female runners.^4,6 An observational study concluded that, among half-marathon and marathon runners, there was no significant increase in race-related injury, based on BMI.⁹ However, another study showed a higher rate of running-related injury in novice runners who had a higher BMI.¹⁰ A prospective cohort study found that runners with a higher BMI reported increased knee stiffness, which can place a runner at higher risk of overuse injury.⁴

Although these results conflict, there is consistency in the finding that obese novice runners are likely at increased risk of running-related injury; it is reasonable, therefore, for you to discuss strategies to reduce the risk of other modifiable factors, especially among obese novice runners. Patients with a higher BMI should not be discouraged from running, because exercise in combination with healthy eating habits is essential to decrease the myriad adverse health outcomes associated with obesity.

Female runners with a lower BMI, especially in the presence of other components of the female athlete triad (inadequate nutrition, amenorrhea, and low bone density), should be counseled about their increased risk of bone stress injury.²¹ Notably, a study of female US Navy recruits randomized to receive a trial of dietary supplementation of vitamin D plus calcium, or placebo, showed a 21% lower incidence of bone stress injury in the active-treatment group.²² To mitigate risk of injury associated with low BMI and the female athlete triad, therefore, a multidisciplinary approach of nutrition intervention, dietary optimization of vitamin D and calcium, and, possibly, activity modification should be implemented when appropriate.

Running gait. A study using 2-dimensional gait analysis to visualize biomechanical running patterns in injured and noninjured runners found that, in regard to mechanical variables, running-related injury was most strongly associated with contralateral pelvic drop.²³ Gait retraining can be employed to help decrease contralateral pelvic drop.²⁴ In addition, pelvic drop is often a result of weak gluteal muscles, and can be improved by doing strengthening exercises at home or with physical therapy.

Longer stride is also associated with running-related injury.²⁵ A study showed improvement in patellofemoral pain by having runners increase stride rate by 10%, which reduces stride length to a significant degree.^25,26 These improvements were maintained at 1-month and 3-month follow-up, and required only 1 gait retraining session.

Continue to: Get analysis is not feasible...

Gait analysis is not feasible in most primary care clinics. Instead, patients who run and (1) in whom pain persists despite more traditional treatments and (2) who have had recurring injury should be referred to a gait lab for analysis, usually by a physical therapist.

Nonmodifiable risk factors

Arch height. A high arch (pes cavus) is associated with increased risk of running-related injury, including bone stress injury, Achilles tendinopathy, plantar fasciitis, and patellofemoral pain syndrome.⁵ The mechanism of injury is thought to be increased forefoot loading forces.¹

A review article showed that patients with pes cavus have reduced pain when using an orthosis, although there is no associated decrease in the risk of injury.⁵ To the contrary, a prospective study concluded that arch height was unrelated to increased risk of running-related injury.⁷

A study showed improvement in patellofemoral pain by having runners increase stride rate by 10%, which reduces stride length to a significant degree.

Evidence regarding flat feet (pes planus) and risk of injury is also mixed. Some studies show that pes planus is not associated with increased risk of injury in athletes.¹² A cross-sectional study in older patients showed those with pes planus morphology had a higher rate of knee pain and wearing away of medial compartment cartilage.¹³ Because this study comprised only older adults, it is not generalizable to runners—nor can conclusions be drawn about causation, given the cross-sectional nature of the study.

Although a foot orthosis can correct mechanical differences caused by pes planus morphology, there is not enough evidence to conclude that correction results in a lower rate of injury. In sum, data are mixed with regard to arch height as a risk factor for running-related injury.

Continue to: Patients with...

Patients with pes planus or pes cavus should not be discouraged from running, however. If they experience pain with running, they might benefit from a trial of arch support inserts; or consider referral to an orthotist for evaluation for a custom orthosis.

Sex. Based on a prospective cohort study, female runners have a slightly higher rate of running injury than male counterparts.⁴ Similarly, a study showed that female military members generally had a higher incidence of stress fractures than male military members—specifically, femoral shaft and neck stress fractures.¹⁴ Runners who fall in the spectrum of the female athlete triad, as described earlier, are particularly vulnerable to bone stress injury. It is reasonable, therefore, to review risk factors for injury with female runners (as it is with all runners), especially those who have sustained a prior running-related injury.

Increased Q-angle (an obsolete risk factor). The Q-angle is approximated by drawing a line from the anterior superior iliac spine to the patella and a second line from the patella to the tibial tubercle. In males, a normal Q-angle is 14°; in females, 17° (SD = 4.5°). The Q-angle can be obtained by goniometric or radiographic measurement.

An increased Q-angle had been considered an intrinsic risk factor for running injury but has not been shown to be associated with increased risk of running-related injury or patellofemoral pain syndrome.^27,28 Because the Q-angle is not a clinically relevant tool in assessing risk of injury, do not routinely measure it or include it in risk-factor counseling.

OA. Based on a systematic review of observational studies, data are inconclusive with regard to whether running contributes to, or is protective against, knee OA.¹⁵ In a large cohort study, running (1) was protective against development of hip OA and (2) decreased the risk of requiring hip replacement.²⁹ This finding was supported by animal-model research that concluded that it is inactivity that results in thinning of articular cartilage.²⁹ In addition, a systematic review of randomized controlled trials concluded that knee joint-loading exercises are not harmful to articular cartilage (this is low-quality evidence, however).¹⁶

Continue to: Given that there...

Given that there are no high-quality studies suggesting that running contributes to or exacerbates OA, patients with OA can be counseled to start or continue running as tolerated because the health benefit of running likely outweighs risk. Patients with pre-existing moderate-to-severe OA might report knee and hip pain that is already exacerbated by certain activities; if a high-impact activity, such as running, makes that pain worse, exercise counseling that you provide can be tailored to include lower-impact alternatives, such as swimming, cycling, or an elliptical workout.

CASE

In response to Ms. K’s interest in beginning an exercise regimen that includes running, you perform a complete routine pre-participation evaluation and appropriate cardiac screening. You discuss risk factors for running injury, focusing on modifiable risk factors.

High-mileage running, especially > 40 miles per week, is associated with increased risk of injury, most often of the hip and hamstring.

Ms. K is perimenopausal but reports a history of regular menstrual cycles. She eats a relatively well-balanced diet. You advise that her BMI should not restrict her from incorporating running into her fitness regimen. Also, you reassure her that she should not restrict running based on a diagnosis of OA; instead, you advise her to monitor her symptoms and reconsider her program if running makes her knee pain worse.

At this point, Ms. K is ready to run. She tells you that, based on your guidance, she feels more comfortable and safe starting a running program.

Preventing injury

After reviewing risk factors for running-­related injury with patients, encourage other evidence-based methods of reducing that risk.

Continue to: Shoes

 

 

Shoes

The running shoe industry offers a variety of running shoes, from minimalist shoes to cushioned stability shoes that vary based on the amount of cushioning, level of motion control, and amount of heel-to-toe drop. With so many options, new runners might wonder which shoes can reduce their risk of injury and how they should select a pair.

Stability. A characteristic of running shoes promoted by the industry is their stability: ie, their motion control. Stability shoes are marketed to runners who overpronate and therefore limit motion to prevent overpronation. The benefit of stability shoes, or stability insoles, is unclear.³⁰ A randomized controlled trial showed that, in runners who overpronate, motion-control shoes reduced their risk of injury.³¹ However, another study assessed whether shoes that had been “prescribed” based on foot morphology and stride reduced the risk of injury (compared to neutral, cushioned shoes) and found no change in the incidence of soft-tissue injury.³² Given no strong evidence to suggest otherwise, runners can be advised to buy shoes based on comfort rather than on foot morphology or running stride.

Heel-to-toe drop. Another component of shoe variability is heel-to-toe drop (the height difference between heel and forefoot). A study suggests that moderate-to-high (8-12 mm) heel-to-toe drop is associated with a reduced risk of running injury.³³ Barefoot running shoes, which, typically, have no heel-to-toe drop, are associated with increased risk of injury—specifically, foot stress fracture (especially in runners who are even moderately overweight).^34,35

Shoe age and shoe wear can be modified to reduce injury. There is evidence that running shoes lose approximately 50% of cushioning after 300 to 500 miles of use.³⁶ Another study found that rotating running shoes—ideally, different types or brands—can lead to fewer running-related injuries.³⁷

In general, patients can be counseled to use shoes that feel comfortable, as long as they replace them regularly (TABLE 2). Runners can also consider alternating pairs of different running shoes between runs. Overweight runners should avoid minimally cushioned and low heel-to-toe drop running shoes.

Continue to: Cross-training

 

 

Cross-training

Cross-training exercises for runners include cycling, an elliptical workout, swimming, and weightlifting. Incorporating cross-­training can be protective against running injury because cross-training requires different movement patterns, prevents overuse, and equalizes muscle imbalances that occur with running.⁷ In addition, replacing running with a cross-training activity can decrease weekly running time and mileage, which can further reduce risk of running-related injury.⁷ Runners—especially higher-mileage runners—should be encouraged to incorporate cross-training into their workout regimen to decrease their risk of injury.

There is no reason to counsel runners to run on a softer running surface, unless they find that doing so is more comfortable.

Stretching. The authors of a Cochrane review concluded that there is no significant reduction in injury associated with hamstring or gastrocnemius stretching.³² A small randomized, controlled, crossover study concluded that participants subjectively felt their performance was better when warm-ups included stretching.³⁸ This perceived improvement in performance was similar between groups who completed dynamic or static stretching. However, no difference was noted in flexibility or objective performance between groups who stretched or did not stretch before activity.

Although there is no supporting evidence that stretching reduces the risk of injury, stretching is a low-risk intervention. Because stretching might provide subjective benefit to runners, you need not discourage patients from including this activity in their running program.

CORRESPONDENCE
Kartik Sidhar, MD, 15370 Huff Way, Brookfield, WI, 53005; kartiksidhar@gmail.com

Approximately 60 million people in the United States run for exercise at least once a calendar year, with approximately 11 million of them running > 100 days a year.^1,2 Running is an affordable, convenient, and efficient form of exercise, whose benefits include a decrease in the risk of all-cause early mortality, cancer, and diabetes; an improved lipid profile; and better mental health.³

However, running is also the cause of a significant percentage of exercise-associated injuries: More than 60% of runners report overuse injury annually.⁴ Given the high incidence of running-related injury, an important component of primary care is accurately diagnosing and managing such injuries and counseling patients about how to prevent them.

This article reviews risk factors for running-related injury and summarizes evidence-based recommendations for prevention.

CASE

During a health maintenance examination, Clara K, a 47-year-old woman who is obese (body mass index [BMI], 34) and has bilateral knee osteoarthritis (OA), inquires about establishing a weight-loss strategy. Ms. K is interested in starting an exercise regimen involving running but is worried about provoking a flare of OA pain.

Risk factors for running injuries

Several risk factors—some modifiable, others nonmodifiable—are associated with running-related injury (TABLE 1^4-16). In addition, research suggests that other variables once thought to be risk factors, such as running surface and the Q-angle (described later), are not associated with running-related injury.

Modifiable risk factors

Changes in a training regimen or type of training. Many runners escalate training regimens as their fitness improves. Increasing mileage and changing the type of training (such as introducing hills or interval training) are independent risk factors for sustaining injury.⁵

Running is an affordable, convenient, and efficient form of exercise; however, more than 60% of runners report overuse injury annually.

The traditional recommendation has been for a runner to slowly increase or modify training with a 10% weekly increase in mileage or intensity.¹⁷ However, a randomized controlled trial failed to show a lower incidence of injury among amateur runners who adopted a graded exercise program.¹⁸ Regardless: It is still prudent to recommend a gradual increase in activity, such as taking ≥ 1 day off between running workouts or starting with a walking or jogging program, especially when there is a history of injury.¹⁹

Continue to: Excessive mileage

Excessive mileage. Many runners aspire to complete high-mileage runs. There is low-quality evidence demonstrating that high-mileage running, especially > 40 miles per week, is associated with increased risk of running-related injury.⁵ Injuries that occur with higher mileage are more often those of the hip and hamstring.⁵ A study noted that running ≤ 25 miles a week was protective against calf injury.⁶

Overall, there is little evidence to show that high-mileage running is associated with increased risk of running-related injury. However, this is still a risk factor that you should address with patients who have a running program—especially novices and those who ramp up mileage quickly.

Type of surface. Access to running surfaces—concrete, pavement, trails, treadmills, and athletic tracks—varies by time of day and season. Softer surfaces include treadmill, tracks, and trails; harder surfaces include asphalt and concrete.

There are limited data linking running surface with risk of injury.⁷ A study did not find an association between peak impact force based on running surface⁸; the authors hypothesized that runners compensate for a harder surface by making kinematic adjustments to minimize impact. With no strong evidence to link running-related injury to a particular running surface, patients should not be restricted to a softer running surface unless they notice a difference in comfort, because it is likely that they can compensate for a harder surface by adapting their gait.

Patients can therefore be counseled to run locally on sidewalks and neighborhood streets—if safe to do so—instead of obtaining a gym membership or driving to run on a trail. Such reassurance can increase a patient’s access to running and reduce barriers to exercise.

Continue to: BMI

BMI. Elevated BMI increases joint contact forces, which might increase risk of pain and injury.²⁰ Results of studies investigating the link between BMI and running injury are mixed; some report that, in regard to bone stress injury, overweight BMI (> 25) is a risk factor for male runners and underweight BMI (< 18.5) is a risk factor for female runners.^4,6 An observational study concluded that, among half-marathon and marathon runners, there was no significant increase in race-related injury, based on BMI.⁹ However, another study showed a higher rate of running-related injury in novice runners who had a higher BMI.¹⁰ A prospective cohort study found that runners with a higher BMI reported increased knee stiffness, which can place a runner at higher risk of overuse injury.⁴

Although these results conflict, there is consistency in the finding that obese novice runners are likely at increased risk of running-related injury; it is reasonable, therefore, for you to discuss strategies to reduce the risk of other modifiable factors, especially among obese novice runners. Patients with a higher BMI should not be discouraged from running, because exercise in combination with healthy eating habits is essential to decrease the myriad adverse health outcomes associated with obesity.

Female runners with a lower BMI, especially in the presence of other components of the female athlete triad (inadequate nutrition, amenorrhea, and low bone density), should be counseled about their increased risk of bone stress injury.²¹ Notably, a study of female US Navy recruits randomized to receive a trial of dietary supplementation of vitamin D plus calcium, or placebo, showed a 21% lower incidence of bone stress injury in the active-treatment group.²² To mitigate risk of injury associated with low BMI and the female athlete triad, therefore, a multidisciplinary approach of nutrition intervention, dietary optimization of vitamin D and calcium, and, possibly, activity modification should be implemented when appropriate.

Running gait. A study using 2-dimensional gait analysis to visualize biomechanical running patterns in injured and noninjured runners found that, in regard to mechanical variables, running-related injury was most strongly associated with contralateral pelvic drop.²³ Gait retraining can be employed to help decrease contralateral pelvic drop.²⁴ In addition, pelvic drop is often a result of weak gluteal muscles, and can be improved by doing strengthening exercises at home or with physical therapy.

Longer stride is also associated with running-related injury.²⁵ A study showed improvement in patellofemoral pain by having runners increase stride rate by 10%, which reduces stride length to a significant degree.^25,26 These improvements were maintained at 1-month and 3-month follow-up, and required only 1 gait retraining session.

Continue to: Get analysis is not feasible...

Gait analysis is not feasible in most primary care clinics. Instead, patients who run and (1) in whom pain persists despite more traditional treatments and (2) who have had recurring injury should be referred to a gait lab for analysis, usually by a physical therapist.

Nonmodifiable risk factors

Arch height. A high arch (pes cavus) is associated with increased risk of running-related injury, including bone stress injury, Achilles tendinopathy, plantar fasciitis, and patellofemoral pain syndrome.⁵ The mechanism of injury is thought to be increased forefoot loading forces.¹

A review article showed that patients with pes cavus have reduced pain when using an orthosis, although there is no associated decrease in the risk of injury.⁵ To the contrary, a prospective study concluded that arch height was unrelated to increased risk of running-related injury.⁷

A study showed improvement in patellofemoral pain by having runners increase stride rate by 10%, which reduces stride length to a significant degree.

Evidence regarding flat feet (pes planus) and risk of injury is also mixed. Some studies show that pes planus is not associated with increased risk of injury in athletes.¹² A cross-sectional study in older patients showed those with pes planus morphology had a higher rate of knee pain and wearing away of medial compartment cartilage.¹³ Because this study comprised only older adults, it is not generalizable to runners—nor can conclusions be drawn about causation, given the cross-sectional nature of the study.

Although a foot orthosis can correct mechanical differences caused by pes planus morphology, there is not enough evidence to conclude that correction results in a lower rate of injury. In sum, data are mixed with regard to arch height as a risk factor for running-related injury.

Continue to: Patients with...

Patients with pes planus or pes cavus should not be discouraged from running, however. If they experience pain with running, they might benefit from a trial of arch support inserts; or consider referral to an orthotist for evaluation for a custom orthosis.

Sex. Based on a prospective cohort study, female runners have a slightly higher rate of running injury than male counterparts.⁴ Similarly, a study showed that female military members generally had a higher incidence of stress fractures than male military members—specifically, femoral shaft and neck stress fractures.¹⁴ Runners who fall in the spectrum of the female athlete triad, as described earlier, are particularly vulnerable to bone stress injury. It is reasonable, therefore, to review risk factors for injury with female runners (as it is with all runners), especially those who have sustained a prior running-related injury.

Increased Q-angle (an obsolete risk factor). The Q-angle is approximated by drawing a line from the anterior superior iliac spine to the patella and a second line from the patella to the tibial tubercle. In males, a normal Q-angle is 14°; in females, 17° (SD = 4.5°). The Q-angle can be obtained by goniometric or radiographic measurement.

An increased Q-angle had been considered an intrinsic risk factor for running injury but has not been shown to be associated with increased risk of running-related injury or patellofemoral pain syndrome.^27,28 Because the Q-angle is not a clinically relevant tool in assessing risk of injury, do not routinely measure it or include it in risk-factor counseling.

OA. Based on a systematic review of observational studies, data are inconclusive with regard to whether running contributes to, or is protective against, knee OA.¹⁵ In a large cohort study, running (1) was protective against development of hip OA and (2) decreased the risk of requiring hip replacement.²⁹ This finding was supported by animal-model research that concluded that it is inactivity that results in thinning of articular cartilage.²⁹ In addition, a systematic review of randomized controlled trials concluded that knee joint-loading exercises are not harmful to articular cartilage (this is low-quality evidence, however).¹⁶

Continue to: Given that there...

Given that there are no high-quality studies suggesting that running contributes to or exacerbates OA, patients with OA can be counseled to start or continue running as tolerated because the health benefit of running likely outweighs risk. Patients with pre-existing moderate-to-severe OA might report knee and hip pain that is already exacerbated by certain activities; if a high-impact activity, such as running, makes that pain worse, exercise counseling that you provide can be tailored to include lower-impact alternatives, such as swimming, cycling, or an elliptical workout.

CASE

In response to Ms. K’s interest in beginning an exercise regimen that includes running, you perform a complete routine pre-participation evaluation and appropriate cardiac screening. You discuss risk factors for running injury, focusing on modifiable risk factors.

High-mileage running, especially > 40 miles per week, is associated with increased risk of injury, most often of the hip and hamstring.

Ms. K is perimenopausal but reports a history of regular menstrual cycles. She eats a relatively well-balanced diet. You advise that her BMI should not restrict her from incorporating running into her fitness regimen. Also, you reassure her that she should not restrict running based on a diagnosis of OA; instead, you advise her to monitor her symptoms and reconsider her program if running makes her knee pain worse.

At this point, Ms. K is ready to run. She tells you that, based on your guidance, she feels more comfortable and safe starting a running program.

Preventing injury

After reviewing risk factors for running-­related injury with patients, encourage other evidence-based methods of reducing that risk.

Continue to: Shoes

 

 

Shoes

The running shoe industry offers a variety of running shoes, from minimalist shoes to cushioned stability shoes that vary based on the amount of cushioning, level of motion control, and amount of heel-to-toe drop. With so many options, new runners might wonder which shoes can reduce their risk of injury and how they should select a pair.

Stability. A characteristic of running shoes promoted by the industry is their stability: ie, their motion control. Stability shoes are marketed to runners who overpronate and therefore limit motion to prevent overpronation. The benefit of stability shoes, or stability insoles, is unclear.³⁰ A randomized controlled trial showed that, in runners who overpronate, motion-control shoes reduced their risk of injury.³¹ However, another study assessed whether shoes that had been “prescribed” based on foot morphology and stride reduced the risk of injury (compared to neutral, cushioned shoes) and found no change in the incidence of soft-tissue injury.³² Given no strong evidence to suggest otherwise, runners can be advised to buy shoes based on comfort rather than on foot morphology or running stride.

Heel-to-toe drop. Another component of shoe variability is heel-to-toe drop (the height difference between heel and forefoot). A study suggests that moderate-to-high (8-12 mm) heel-to-toe drop is associated with a reduced risk of running injury.³³ Barefoot running shoes, which, typically, have no heel-to-toe drop, are associated with increased risk of injury—specifically, foot stress fracture (especially in runners who are even moderately overweight).^34,35

Shoe age and shoe wear can be modified to reduce injury. There is evidence that running shoes lose approximately 50% of cushioning after 300 to 500 miles of use.³⁶ Another study found that rotating running shoes—ideally, different types or brands—can lead to fewer running-related injuries.³⁷

In general, patients can be counseled to use shoes that feel comfortable, as long as they replace them regularly (TABLE 2). Runners can also consider alternating pairs of different running shoes between runs. Overweight runners should avoid minimally cushioned and low heel-to-toe drop running shoes.

Continue to: Cross-training

 

 

Cross-training

Cross-training exercises for runners include cycling, an elliptical workout, swimming, and weightlifting. Incorporating cross-­training can be protective against running injury because cross-training requires different movement patterns, prevents overuse, and equalizes muscle imbalances that occur with running.⁷ In addition, replacing running with a cross-training activity can decrease weekly running time and mileage, which can further reduce risk of running-related injury.⁷ Runners—especially higher-mileage runners—should be encouraged to incorporate cross-training into their workout regimen to decrease their risk of injury.

There is no reason to counsel runners to run on a softer running surface, unless they find that doing so is more comfortable.

Stretching. The authors of a Cochrane review concluded that there is no significant reduction in injury associated with hamstring or gastrocnemius stretching.³² A small randomized, controlled, crossover study concluded that participants subjectively felt their performance was better when warm-ups included stretching.³⁸ This perceived improvement in performance was similar between groups who completed dynamic or static stretching. However, no difference was noted in flexibility or objective performance between groups who stretched or did not stretch before activity.

Although there is no supporting evidence that stretching reduces the risk of injury, stretching is a low-risk intervention. Because stretching might provide subjective benefit to runners, you need not discourage patients from including this activity in their running program.

CORRESPONDENCE
Kartik Sidhar, MD, 15370 Huff Way, Brookfield, WI, 53005; kartiksidhar@gmail.com

High adolescent body mass index is tied to increasing risks of stroke in young adulthood in both men and women, results of a large, population-based cohort study show.

Copyright American Stroke Association

High and even high-normal body mass index (BMI) were linked to increased ischemic stroke risk, regardless of whether or not individuals had diabetes.

Overweight and obese adolescent groups in the study had a roughly two- to threefold increased risk of ischemic stroke, which was apparent even before age 30 years in the study that was based on records of Israeli adolescents evaluated prior to mandatory military service.

These findings highlight the importance of treating and preventing high BMI among adolescence, study coauthor Gilad Twig, MD, MPH, PhD, said in a press release.

“Adults who survive stroke earlier in life face poor functional outcomes, which can lead to unemployment, depression and anxiety,” said Dr. Twig, associate professor in the department of military medicine in The Hebrew University in Jerusalem.

The costs of stroke prevention and care, already high, are expected to become even higher as the adolescent obesity prevalence goes up, fueling further increases in stroke rate, Dr. Twig added.

This is believed to be the first study showing that stroke risk is associated with higher BMI values in both men and women, not just men, Dr. Twig and coauthors said in their article, published May 13, 2021 in the journal Stroke. Previous studies assessing the stroke-BMI relationship in adolescents were based on records of Swedish men evaluated during military conscription at age 18.

In the present study, Dr. Twig and coauthors assessed the linkage between adolescent BMI and first stroke event in 1.9 million male and female adolescents in Israel who were evaluated 1 year prior to mandatory military service, between the years of 1985 and 2013.

They cross-referenced that information with stroke events in a national registry to which all hospitals in Israel are required to report.

The adolescents were about 17 years of age on average at the time of evaluation, 58% were male, and 84% were born in Israel. The mean age at the beginning of follow-up for stroke was about 31 years.

Over the follow-up period, investigators identified 1,088 first stroke events, including 921 ischemic and 167 hemorrhagic strokes.

A gradual increase in stroke rate was seen across BMI categories for ischemic strokes, but not so much for hemorrhagic strokes, investigators found.

Hazard ratios for first ischemic stroke event were 1.4 (95% confidence interval, 1.2-1.6) for the high-normal BMI group, 2.0 (95% CI, 1.6-2.4) for the overweight group, and 3.5 (95% CI, 2.8-4.5) for the obese group after adjusting for age and sex at beginning of follow-up, investigators reported.

When the adjusted results were stratified by presence or absence of diabetes, estimates were similar to what was seen in the overall risk model, they added.

Among those young adults who developed ischemic stroke, 43% smoked, 29% had high blood pressure, 17% had diabetes, and 32% had abnormal lipids at the time of diagnosis, the reported data showed.

The clinical and public health implications of these findings could be substantial, since strokes are associated with worse medical and socioeconomic outcomes in younger as compared with older individuals, according to Dr. Twig and coauthors.

Younger individuals with stroke have a higher risk of recurrent stroke, heart attack, long-term care, or death, they said. Moreover, about half of young-adult stroke survivors have poor functional outcomes, and their risk of unemployment and depression/anxiety is higher than in young individuals without stroke.

One limitation of the study is that follow-up BMI data were not available for all participants. As a result, the contribution of obesity to stroke risk over time could not be assessed, and the independent risk of BMI during adolescence could not be determined. In addition, the authors said the study underrepresents orthodox and ultraorthodox Jewish women, as they are not obligated to serve in the Israeli military.

The study authors had no disclosures related to the study, which was supported by a medical corps Israel Defense Forces research grant.

High adolescent body mass index is tied to increasing risks of stroke in young adulthood in both men and women, results of a large, population-based cohort study show.

Copyright American Stroke Association

High and even high-normal body mass index (BMI) were linked to increased ischemic stroke risk, regardless of whether or not individuals had diabetes.

Overweight and obese adolescent groups in the study had a roughly two- to threefold increased risk of ischemic stroke, which was apparent even before age 30 years in the study that was based on records of Israeli adolescents evaluated prior to mandatory military service.

These findings highlight the importance of treating and preventing high BMI among adolescence, study coauthor Gilad Twig, MD, MPH, PhD, said in a press release.

“Adults who survive stroke earlier in life face poor functional outcomes, which can lead to unemployment, depression and anxiety,” said Dr. Twig, associate professor in the department of military medicine in The Hebrew University in Jerusalem.

The costs of stroke prevention and care, already high, are expected to become even higher as the adolescent obesity prevalence goes up, fueling further increases in stroke rate, Dr. Twig added.

This is believed to be the first study showing that stroke risk is associated with higher BMI values in both men and women, not just men, Dr. Twig and coauthors said in their article, published May 13, 2021 in the journal Stroke. Previous studies assessing the stroke-BMI relationship in adolescents were based on records of Swedish men evaluated during military conscription at age 18.

In the present study, Dr. Twig and coauthors assessed the linkage between adolescent BMI and first stroke event in 1.9 million male and female adolescents in Israel who were evaluated 1 year prior to mandatory military service, between the years of 1985 and 2013.

They cross-referenced that information with stroke events in a national registry to which all hospitals in Israel are required to report.

The adolescents were about 17 years of age on average at the time of evaluation, 58% were male, and 84% were born in Israel. The mean age at the beginning of follow-up for stroke was about 31 years.

Over the follow-up period, investigators identified 1,088 first stroke events, including 921 ischemic and 167 hemorrhagic strokes.

A gradual increase in stroke rate was seen across BMI categories for ischemic strokes, but not so much for hemorrhagic strokes, investigators found.

Hazard ratios for first ischemic stroke event were 1.4 (95% confidence interval, 1.2-1.6) for the high-normal BMI group, 2.0 (95% CI, 1.6-2.4) for the overweight group, and 3.5 (95% CI, 2.8-4.5) for the obese group after adjusting for age and sex at beginning of follow-up, investigators reported.

When the adjusted results were stratified by presence or absence of diabetes, estimates were similar to what was seen in the overall risk model, they added.

Among those young adults who developed ischemic stroke, 43% smoked, 29% had high blood pressure, 17% had diabetes, and 32% had abnormal lipids at the time of diagnosis, the reported data showed.

The clinical and public health implications of these findings could be substantial, since strokes are associated with worse medical and socioeconomic outcomes in younger as compared with older individuals, according to Dr. Twig and coauthors.

Younger individuals with stroke have a higher risk of recurrent stroke, heart attack, long-term care, or death, they said. Moreover, about half of young-adult stroke survivors have poor functional outcomes, and their risk of unemployment and depression/anxiety is higher than in young individuals without stroke.

One limitation of the study is that follow-up BMI data were not available for all participants. As a result, the contribution of obesity to stroke risk over time could not be assessed, and the independent risk of BMI during adolescence could not be determined. In addition, the authors said the study underrepresents orthodox and ultraorthodox Jewish women, as they are not obligated to serve in the Israeli military.

The study authors had no disclosures related to the study, which was supported by a medical corps Israel Defense Forces research grant.

High adolescent body mass index is tied to increasing risks of stroke in young adulthood in both men and women, results of a large, population-based cohort study show.

Copyright American Stroke Association

High and even high-normal body mass index (BMI) were linked to increased ischemic stroke risk, regardless of whether or not individuals had diabetes.

Overweight and obese adolescent groups in the study had a roughly two- to threefold increased risk of ischemic stroke, which was apparent even before age 30 years in the study that was based on records of Israeli adolescents evaluated prior to mandatory military service.

These findings highlight the importance of treating and preventing high BMI among adolescence, study coauthor Gilad Twig, MD, MPH, PhD, said in a press release.

“Adults who survive stroke earlier in life face poor functional outcomes, which can lead to unemployment, depression and anxiety,” said Dr. Twig, associate professor in the department of military medicine in The Hebrew University in Jerusalem.

The costs of stroke prevention and care, already high, are expected to become even higher as the adolescent obesity prevalence goes up, fueling further increases in stroke rate, Dr. Twig added.

This is believed to be the first study showing that stroke risk is associated with higher BMI values in both men and women, not just men, Dr. Twig and coauthors said in their article, published May 13, 2021 in the journal Stroke. Previous studies assessing the stroke-BMI relationship in adolescents were based on records of Swedish men evaluated during military conscription at age 18.

In the present study, Dr. Twig and coauthors assessed the linkage between adolescent BMI and first stroke event in 1.9 million male and female adolescents in Israel who were evaluated 1 year prior to mandatory military service, between the years of 1985 and 2013.

They cross-referenced that information with stroke events in a national registry to which all hospitals in Israel are required to report.

The adolescents were about 17 years of age on average at the time of evaluation, 58% were male, and 84% were born in Israel. The mean age at the beginning of follow-up for stroke was about 31 years.

Over the follow-up period, investigators identified 1,088 first stroke events, including 921 ischemic and 167 hemorrhagic strokes.

A gradual increase in stroke rate was seen across BMI categories for ischemic strokes, but not so much for hemorrhagic strokes, investigators found.

Hazard ratios for first ischemic stroke event were 1.4 (95% confidence interval, 1.2-1.6) for the high-normal BMI group, 2.0 (95% CI, 1.6-2.4) for the overweight group, and 3.5 (95% CI, 2.8-4.5) for the obese group after adjusting for age and sex at beginning of follow-up, investigators reported.

When the adjusted results were stratified by presence or absence of diabetes, estimates were similar to what was seen in the overall risk model, they added.

Among those young adults who developed ischemic stroke, 43% smoked, 29% had high blood pressure, 17% had diabetes, and 32% had abnormal lipids at the time of diagnosis, the reported data showed.

The clinical and public health implications of these findings could be substantial, since strokes are associated with worse medical and socioeconomic outcomes in younger as compared with older individuals, according to Dr. Twig and coauthors.

Younger individuals with stroke have a higher risk of recurrent stroke, heart attack, long-term care, or death, they said. Moreover, about half of young-adult stroke survivors have poor functional outcomes, and their risk of unemployment and depression/anxiety is higher than in young individuals without stroke.

One limitation of the study is that follow-up BMI data were not available for all participants. As a result, the contribution of obesity to stroke risk over time could not be assessed, and the independent risk of BMI during adolescence could not be determined. In addition, the authors said the study underrepresents orthodox and ultraorthodox Jewish women, as they are not obligated to serve in the Israeli military.

The study authors had no disclosures related to the study, which was supported by a medical corps Israel Defense Forces research grant.

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

mzoler@mdedge.com

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

mzoler@mdedge.com

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

mzoler@mdedge.com

The obesity epidemic in the United States may be slowing improvements in cancer mortality, according to a new analysis of over 50 million cancer and heart disease deaths.

“By integrating 20 years of cancer mortality data, we demonstrated that trends in obesity-associated cancer mortality showed signs of recent deceleration, consistent with recent findings for heart disease mortality,” Christy L. Avery, PhD, and associates wrote in JAMA Network Open.

Improvements in mortality related to heart disease slowed after 2011, a phenomenon that has been associated with rising obesity rates. The age-adjusted mortality rate (AAMR) declined at an average of 3.8 deaths per 100,000 persons from 1999 to 2011 but only 0.7 deaths per 100,000 from 2011 to 2018, based on data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER).

To understand trends in cancer mortality and their possible connection with obesity, data for 1999-2018 from the WONDER database were divided into obesity-associated and non–obesity-associated categories and compared with heart disease mortality, they explained. The database included more than 50 million deaths that matched inclusion criteria.

The analysis showed there was difference between obesity-associated and non–obesity-associated cancers that was obscured when all cancer deaths were considered together. The average annual change in AAMR for obesity-associated cancers slowed from –1.19 deaths per 100,000 in 1999-2011 to –0.83 in 2011-2018, Dr. Avery and associates reported.

For non–obesity-associated cancers, the annual change in AAMR increased from –1.62 per 100,000 for 1999-2011 to –2.29 for 2011-2018, following the trend for all cancers: –1.48 per 100,000 during 1999-2011 and –1.77 in 2011-2018, they said.

“The largest mortality decreases were observed for melanoma of the skin and lung cancer, two cancers not associated with obesity. For obesity-associated cancers, stable or increasing mortality rates have been observed for liver and pancreatic cancer among both men and women as well as for uterine cancer among women,” the investigators wrote.

Demographically, however, the slowing improvement in mortality for obesity-associated cancers did not follow the trend for heart disease. The deceleration for cancer was more pronounced for women and for non-Hispanic Whites and not seen at all in non-Hispanic Asian/Pacific Islander individuals. “For heart disease, evidence of a deceleration was consistent across sex, race, and ethnicity,” they said.

There are “longstanding disparities in obesity” among various populations in the United States, and the recent trend of obesity occurring earlier in life may be having an effect. “Whether the findings of decelerating mortality rates potentially signal a changing profile of cancer and heart disease mortality as the consequences of the obesity epidemic are realized remains to be seen,” they concluded.

The investigators reported receiving grants from the National Institutes of Health during the conduct of the study, but no other disclosures were reported.

rfranki@mdedge.com

The obesity epidemic in the United States may be slowing improvements in cancer mortality, according to a new analysis of over 50 million cancer and heart disease deaths.

“By integrating 20 years of cancer mortality data, we demonstrated that trends in obesity-associated cancer mortality showed signs of recent deceleration, consistent with recent findings for heart disease mortality,” Christy L. Avery, PhD, and associates wrote in JAMA Network Open.

Improvements in mortality related to heart disease slowed after 2011, a phenomenon that has been associated with rising obesity rates. The age-adjusted mortality rate (AAMR) declined at an average of 3.8 deaths per 100,000 persons from 1999 to 2011 but only 0.7 deaths per 100,000 from 2011 to 2018, based on data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER).

To understand trends in cancer mortality and their possible connection with obesity, data for 1999-2018 from the WONDER database were divided into obesity-associated and non–obesity-associated categories and compared with heart disease mortality, they explained. The database included more than 50 million deaths that matched inclusion criteria.

The analysis showed there was difference between obesity-associated and non–obesity-associated cancers that was obscured when all cancer deaths were considered together. The average annual change in AAMR for obesity-associated cancers slowed from –1.19 deaths per 100,000 in 1999-2011 to –0.83 in 2011-2018, Dr. Avery and associates reported.

For non–obesity-associated cancers, the annual change in AAMR increased from –1.62 per 100,000 for 1999-2011 to –2.29 for 2011-2018, following the trend for all cancers: –1.48 per 100,000 during 1999-2011 and –1.77 in 2011-2018, they said.

“The largest mortality decreases were observed for melanoma of the skin and lung cancer, two cancers not associated with obesity. For obesity-associated cancers, stable or increasing mortality rates have been observed for liver and pancreatic cancer among both men and women as well as for uterine cancer among women,” the investigators wrote.

Demographically, however, the slowing improvement in mortality for obesity-associated cancers did not follow the trend for heart disease. The deceleration for cancer was more pronounced for women and for non-Hispanic Whites and not seen at all in non-Hispanic Asian/Pacific Islander individuals. “For heart disease, evidence of a deceleration was consistent across sex, race, and ethnicity,” they said.

There are “longstanding disparities in obesity” among various populations in the United States, and the recent trend of obesity occurring earlier in life may be having an effect. “Whether the findings of decelerating mortality rates potentially signal a changing profile of cancer and heart disease mortality as the consequences of the obesity epidemic are realized remains to be seen,” they concluded.

The investigators reported receiving grants from the National Institutes of Health during the conduct of the study, but no other disclosures were reported.

rfranki@mdedge.com

The obesity epidemic in the United States may be slowing improvements in cancer mortality, according to a new analysis of over 50 million cancer and heart disease deaths.

“By integrating 20 years of cancer mortality data, we demonstrated that trends in obesity-associated cancer mortality showed signs of recent deceleration, consistent with recent findings for heart disease mortality,” Christy L. Avery, PhD, and associates wrote in JAMA Network Open.

Improvements in mortality related to heart disease slowed after 2011, a phenomenon that has been associated with rising obesity rates. The age-adjusted mortality rate (AAMR) declined at an average of 3.8 deaths per 100,000 persons from 1999 to 2011 but only 0.7 deaths per 100,000 from 2011 to 2018, based on data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER).

To understand trends in cancer mortality and their possible connection with obesity, data for 1999-2018 from the WONDER database were divided into obesity-associated and non–obesity-associated categories and compared with heart disease mortality, they explained. The database included more than 50 million deaths that matched inclusion criteria.

The analysis showed there was difference between obesity-associated and non–obesity-associated cancers that was obscured when all cancer deaths were considered together. The average annual change in AAMR for obesity-associated cancers slowed from –1.19 deaths per 100,000 in 1999-2011 to –0.83 in 2011-2018, Dr. Avery and associates reported.

For non–obesity-associated cancers, the annual change in AAMR increased from –1.62 per 100,000 for 1999-2011 to –2.29 for 2011-2018, following the trend for all cancers: –1.48 per 100,000 during 1999-2011 and –1.77 in 2011-2018, they said.

“The largest mortality decreases were observed for melanoma of the skin and lung cancer, two cancers not associated with obesity. For obesity-associated cancers, stable or increasing mortality rates have been observed for liver and pancreatic cancer among both men and women as well as for uterine cancer among women,” the investigators wrote.

Demographically, however, the slowing improvement in mortality for obesity-associated cancers did not follow the trend for heart disease. The deceleration for cancer was more pronounced for women and for non-Hispanic Whites and not seen at all in non-Hispanic Asian/Pacific Islander individuals. “For heart disease, evidence of a deceleration was consistent across sex, race, and ethnicity,” they said.

There are “longstanding disparities in obesity” among various populations in the United States, and the recent trend of obesity occurring earlier in life may be having an effect. “Whether the findings of decelerating mortality rates potentially signal a changing profile of cancer and heart disease mortality as the consequences of the obesity epidemic are realized remains to be seen,” they concluded.

The investigators reported receiving grants from the National Institutes of Health during the conduct of the study, but no other disclosures were reported.

rfranki@mdedge.com

Scientists have proposed a simple new definition for “metabolically healthy obesity” to identify individuals who do not have an increased risk of cardiovascular disease (CVD) death and total mortality.

The team – led by Anika Zembic, MPH, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany – performed an assessment of anthropometric and metabolic risk factors as well as mortality data from two cohorts that “yielded a simple definition to categorize participants with obesity as metabolically healthy or unhealthy.”

They defined “metabolically healthy” as systolic blood pressure <130 mm Hg and no use of blood pressure-lowering medication; waist-to-hip ratio <0.95 (in women) and <1.03 (in men); and no prevalent type 2 diabetes.

Based on this new definition, 42% of participants in the third U.S. National Health and Nutrition Examination Survey (NHANES-III) and 19% of participants in the UK Biobank study had metabolically healthy obesity and did not have an increased risk for CVD mortality and total mortality compared with individuals with metabolically healthy normal weight.  

“People with a phenotype defined as metabolically unhealthy using this definition had significantly higher hazard ratios for [CVD] mortality and total mortality irrespective of body mass index category, and people with phenotypes defined as having metabolically healthy obesity displayed no increased risk,” the researchers noted in their article, published May 7 in JAMA Network Open.

“Our new definition may be important not only to stratify risk of mortality in people with obesity, but also in people with overweight and normal weight,” they concluded.
 

Thirty different definitions of ‘metabolically healthy obesity’

“To date, there is no universally accepted standard for defining [metabolically healthy obesity] and more than 30 different definitions have been used to operationalize the phenotypes in studies,” which may explain the “continued unresolved debate” about outcomes in patients with metabolically unhealthy obesity, Ayana K. April-Sanders, PhD, and Carlos J. Rodriguez, MD, MPH, from Albert Einstein College of Medicine, New York, wrote in an accompanying commentary.

The current study, they noted, suggests that waist-to-hip ratio is a better measure of central adiposity than waist circumference, and that the effect of dyslipidemia on CVD mortality may be weaker among individuals with obesity.

However, the findings may not be generalizable to other CVD outcomes, they cautioned.

And importantly, some individuals with metabolically healthy obesity will likely transition to unhealthy obesity over time due to weight gain, aging, and lack of physical activity.

Therefore, “the present study provides a prototype of how that definition can be derived, but more rigorous tests and evidence using similar techniques are needed, particularly in prospective studies,” according to Dr. April-Sanders and Dr. Rodriguez.

They call for more research to establish a standardized definition of metabolically healthy obesity and then, using that definition, to determine the prevalence of healthy and unhealthy obesity and identify factors that preserve healthy obesity. 
 

Definition developed from NHANES cohort, validated in UK biobank

Ms. Zembic and colleagues explained that previous definitions for metabolically healthy obesity were mainly based on the absence of either metabolic syndrome or insulin resistance, but some individuals with obesity but without metabolic disease still have increased risks of CVD mortality and total mortality.

To develop a more precise definition of metabolically healthy obesity, the researchers analyzed data from 12,341 individuals in the United States who participated in NHANES-III, conducted between 1988 and 1994. The individuals were a mean age of 42 and 51% were women, and they were followed for an average of 14.5 years.  

The researchers validated this definition using data from 374,079 individuals in the population-based UK Biobank cohort who were assessed in 2006 to 2010. Those individuals were a mean age of 56 and 55% were women, and they were followed for a mean of 7.8 years.

The combination of systolic blood pressure and waist-to-hip ratio had the strongest association with CVD mortality and total mortality, and the prevalence of type 2 diabetes was also associated with greater risk.

Regardless of BMI, all groups of metabolically unhealthy individuals had increased risks of CVD mortality and total mortality.

The study and some of the researchers were supported by grants from the German Federal Ministry of Education and Research.  

A version of this article first appeared on Medscape.com.

Scientists have proposed a simple new definition for “metabolically healthy obesity” to identify individuals who do not have an increased risk of cardiovascular disease (CVD) death and total mortality.

The team – led by Anika Zembic, MPH, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany – performed an assessment of anthropometric and metabolic risk factors as well as mortality data from two cohorts that “yielded a simple definition to categorize participants with obesity as metabolically healthy or unhealthy.”

They defined “metabolically healthy” as systolic blood pressure <130 mm Hg and no use of blood pressure-lowering medication; waist-to-hip ratio <0.95 (in women) and <1.03 (in men); and no prevalent type 2 diabetes.

Based on this new definition, 42% of participants in the third U.S. National Health and Nutrition Examination Survey (NHANES-III) and 19% of participants in the UK Biobank study had metabolically healthy obesity and did not have an increased risk for CVD mortality and total mortality compared with individuals with metabolically healthy normal weight.  

“People with a phenotype defined as metabolically unhealthy using this definition had significantly higher hazard ratios for [CVD] mortality and total mortality irrespective of body mass index category, and people with phenotypes defined as having metabolically healthy obesity displayed no increased risk,” the researchers noted in their article, published May 7 in JAMA Network Open.

“Our new definition may be important not only to stratify risk of mortality in people with obesity, but also in people with overweight and normal weight,” they concluded.
 

Thirty different definitions of ‘metabolically healthy obesity’

“To date, there is no universally accepted standard for defining [metabolically healthy obesity] and more than 30 different definitions have been used to operationalize the phenotypes in studies,” which may explain the “continued unresolved debate” about outcomes in patients with metabolically unhealthy obesity, Ayana K. April-Sanders, PhD, and Carlos J. Rodriguez, MD, MPH, from Albert Einstein College of Medicine, New York, wrote in an accompanying commentary.

The current study, they noted, suggests that waist-to-hip ratio is a better measure of central adiposity than waist circumference, and that the effect of dyslipidemia on CVD mortality may be weaker among individuals with obesity.

However, the findings may not be generalizable to other CVD outcomes, they cautioned.

And importantly, some individuals with metabolically healthy obesity will likely transition to unhealthy obesity over time due to weight gain, aging, and lack of physical activity.

Therefore, “the present study provides a prototype of how that definition can be derived, but more rigorous tests and evidence using similar techniques are needed, particularly in prospective studies,” according to Dr. April-Sanders and Dr. Rodriguez.

They call for more research to establish a standardized definition of metabolically healthy obesity and then, using that definition, to determine the prevalence of healthy and unhealthy obesity and identify factors that preserve healthy obesity. 
 

Definition developed from NHANES cohort, validated in UK biobank

Ms. Zembic and colleagues explained that previous definitions for metabolically healthy obesity were mainly based on the absence of either metabolic syndrome or insulin resistance, but some individuals with obesity but without metabolic disease still have increased risks of CVD mortality and total mortality.

To develop a more precise definition of metabolically healthy obesity, the researchers analyzed data from 12,341 individuals in the United States who participated in NHANES-III, conducted between 1988 and 1994. The individuals were a mean age of 42 and 51% were women, and they were followed for an average of 14.5 years.  

The researchers validated this definition using data from 374,079 individuals in the population-based UK Biobank cohort who were assessed in 2006 to 2010. Those individuals were a mean age of 56 and 55% were women, and they were followed for a mean of 7.8 years.

The combination of systolic blood pressure and waist-to-hip ratio had the strongest association with CVD mortality and total mortality, and the prevalence of type 2 diabetes was also associated with greater risk.

Regardless of BMI, all groups of metabolically unhealthy individuals had increased risks of CVD mortality and total mortality.

The study and some of the researchers were supported by grants from the German Federal Ministry of Education and Research.  

A version of this article first appeared on Medscape.com.

Scientists have proposed a simple new definition for “metabolically healthy obesity” to identify individuals who do not have an increased risk of cardiovascular disease (CVD) death and total mortality.

The team – led by Anika Zembic, MPH, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany – performed an assessment of anthropometric and metabolic risk factors as well as mortality data from two cohorts that “yielded a simple definition to categorize participants with obesity as metabolically healthy or unhealthy.”

They defined “metabolically healthy” as systolic blood pressure <130 mm Hg and no use of blood pressure-lowering medication; waist-to-hip ratio <0.95 (in women) and <1.03 (in men); and no prevalent type 2 diabetes.

Based on this new definition, 42% of participants in the third U.S. National Health and Nutrition Examination Survey (NHANES-III) and 19% of participants in the UK Biobank study had metabolically healthy obesity and did not have an increased risk for CVD mortality and total mortality compared with individuals with metabolically healthy normal weight.  

“People with a phenotype defined as metabolically unhealthy using this definition had significantly higher hazard ratios for [CVD] mortality and total mortality irrespective of body mass index category, and people with phenotypes defined as having metabolically healthy obesity displayed no increased risk,” the researchers noted in their article, published May 7 in JAMA Network Open.

“Our new definition may be important not only to stratify risk of mortality in people with obesity, but also in people with overweight and normal weight,” they concluded.
 

Thirty different definitions of ‘metabolically healthy obesity’

“To date, there is no universally accepted standard for defining [metabolically healthy obesity] and more than 30 different definitions have been used to operationalize the phenotypes in studies,” which may explain the “continued unresolved debate” about outcomes in patients with metabolically unhealthy obesity, Ayana K. April-Sanders, PhD, and Carlos J. Rodriguez, MD, MPH, from Albert Einstein College of Medicine, New York, wrote in an accompanying commentary.

The current study, they noted, suggests that waist-to-hip ratio is a better measure of central adiposity than waist circumference, and that the effect of dyslipidemia on CVD mortality may be weaker among individuals with obesity.

However, the findings may not be generalizable to other CVD outcomes, they cautioned.

And importantly, some individuals with metabolically healthy obesity will likely transition to unhealthy obesity over time due to weight gain, aging, and lack of physical activity.

Therefore, “the present study provides a prototype of how that definition can be derived, but more rigorous tests and evidence using similar techniques are needed, particularly in prospective studies,” according to Dr. April-Sanders and Dr. Rodriguez.

They call for more research to establish a standardized definition of metabolically healthy obesity and then, using that definition, to determine the prevalence of healthy and unhealthy obesity and identify factors that preserve healthy obesity. 
 

Definition developed from NHANES cohort, validated in UK biobank

Ms. Zembic and colleagues explained that previous definitions for metabolically healthy obesity were mainly based on the absence of either metabolic syndrome or insulin resistance, but some individuals with obesity but without metabolic disease still have increased risks of CVD mortality and total mortality.

To develop a more precise definition of metabolically healthy obesity, the researchers analyzed data from 12,341 individuals in the United States who participated in NHANES-III, conducted between 1988 and 1994. The individuals were a mean age of 42 and 51% were women, and they were followed for an average of 14.5 years.  

The researchers validated this definition using data from 374,079 individuals in the population-based UK Biobank cohort who were assessed in 2006 to 2010. Those individuals were a mean age of 56 and 55% were women, and they were followed for a mean of 7.8 years.

The combination of systolic blood pressure and waist-to-hip ratio had the strongest association with CVD mortality and total mortality, and the prevalence of type 2 diabetes was also associated with greater risk.

Regardless of BMI, all groups of metabolically unhealthy individuals had increased risks of CVD mortality and total mortality.

The study and some of the researchers were supported by grants from the German Federal Ministry of Education and Research.  

A version of this article first appeared on Medscape.com.

Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.

The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.

“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.

But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.

For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
 

Ultrasound shows what inspection can’t

Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.

“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.

“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.

The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”

A possible step toward PCOS

The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.

Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.

“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.

The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).

Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.

mzoler@mdedge.com

Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.

The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.

“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.

But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.

For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
 

Ultrasound shows what inspection can’t

Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.

“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.

“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.

The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”

A possible step toward PCOS

The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.

Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.

“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.

The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).

Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.

mzoler@mdedge.com

Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.

The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.

“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.

But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.

For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
 

Ultrasound shows what inspection can’t

Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.

“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.

“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.

The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”

A possible step toward PCOS

The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.

Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.

“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.

The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).

Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.

mzoler@mdedge.com

For persons with obesity who lost a substantial amount of weight on a low-calorie diet, the combination of exercise and medication significantly improved weight-loss maintenance, and more so than either strategy alone, according to results of a randomized, head-to-head trial.

A year after starting moderate to vigorous exercise coupled with liraglutide treatment, study participants had a weight loss 9.5 kg more than those who received placebo and usual activity, study results show.

Reductions in both weight and fat loss seen with exercise and liraglutide was roughly twice as much as what was achieved at 1 year with the strategies of liraglutide or exercise alone, according to authors of the study, which appears in the New England Journal of Medicine .

Although the findings may not apply to those who can’t or won’t perform moderate to vigorous exercise, the intervention in this study was nevertheless feasible in this group of persons with obesity who had a very low level of fitness, according to the authors.
 

Hope for healthy weight loss maintenance

Investigator Signe S. Torekov, PhD, said in an interview that these results provide hope that more-intensive exercise regimens, with or without medication, can be useful and well accepted among individuals struggling with obesity.

“When we started our study, we were told, ‘you are never going to have people with obesity exercising that much, and for that long’ – but people were actually very happy about the exercise,” said Dr. Torekov, a professor in the department of biomedical sciences at the University of Copenhagen.

“If you actually set up a program where people are monitored and you have a feedback system, then exercise is an excellent component in obesity treatment that should be much more actively used – not only for its weight-lowering component, but also for improving health and quality of life,” she said in an interview.

Weight-management specialist John D. Clark, MD, PhD, said results of this study can be used to help inform patients about how successful different strategies incorporating exercise and medication may be following initial weight loss.

“When patients plateau on a consistent, calorie-restricted dietary plan, we can educate them and manage expectations about what options may be available to them after their initial weight loss,” said Dr. Clark, of the University of Texas, Dallas.

“If the patient’s goal specifically is weight loss at all costs, then I may suggest, ‘let’s consider liraglutide or liraglutide in combination with exercise,’ ” he said in an interview. “Exercise improves body composition, even if it may not on its own be as successful in the next phase of their weight-loss journey, as shown in this study.”
 

Obesity and weight-loss challenges

Although it’s not uncommon for obese patients to lose a large amount of weight, keeping the weight off is frequently a challenge unless the patient follows a structured weight maintenance program, according to Dr. Torekov and coauthors.

The rapid weight regain seen in many obese patients could be a result of reductions in total energy expenditure or increased appetite. Exercise is one strategy to sustain weight loss, though according to the authors, very few studies have looked at exercise in isolation to quantify its contribution to maintenance.

Accordingly, the present study sought to determine whether exercise, medication, or the combination thereof works best to keep weight off.

The study incorporated liraglutide, a GLP-1 receptor agonist indicated for chronic weight management, along with a reduced-calorie diet and increased physical activity, in adults with elevated body mass index and at least one weight-related comorbidity.

The investigator-initiated phase 3 trial included 215 adults with a body mass index of 32-43. Individuals with type 2 diabetes were excluded. All participants followed an 8-week, low-calorie diet comprising 800 calories per day.

Participants who lost 5% or more of their body weight were then randomized to 1 year of exercise plus liraglutide, exercise plus placebo, usual activity plus liraglutide, or usual activity plus placebo.

The exercise program – which was structured but flexible, according to investigators – included group exercise sessions that incorporated 30 minutes of indoor cycling and 15 minutes of circuit training 2 days each week. Participants wore heart rate monitors during exercise to make sure they reached targets for moderate to vigorous intensity.

Instructors trained in exercise physiology planned and monitored individualized exercise programs for each participant in the exercise-medication or exercise-only arms of the study.

Participants in all groups attended 12 one-on-one consultations where body weight was measured and dietetic support was provided.
 

Weight loss with exercise and medication

Out of 215 individuals enrolled in the study, 195 lost at least 5% of body weight and continued on to the randomized portion, the investigators reported. During the diet phase, they lost a mean of 13.1 kg, translating into a 12% mean reduction in body weight.

The mean frequency of exercise was 2.4 times per week in the exercise-plus-medication group and 2.5 times per week in the exercise-only group. About one-third of the exercise took place in the group sessions, and there was no difference in relative intensity between group and individual exercise regimens, the investigators said.

Individuals in the exercise plus medication group continued to lose more weight, such that, at the end of 1 year, the weight loss decreased even further, by a mean of –3.4 kg. By contrast, weight increased by a mean of 6.1 kg for the placebo group, adding up to a treatment difference of –9.5 kg (95% confidence interval, –13.1 to –5.9; P < .001), according to the report.

That treatment effect was also seen, but more muted, in the exercise- and liraglutide-only groups, at –4.1 kg and –6.8 kg, respectively.

A significant treatment effect was observed for exercise plus liraglutide, compared with exercise alone, at –5.4 kg (P = .004), while the treatment effect for the combination versus liraglutide alone was not significant at –2.7 kg (P = .13), the data show.

Body-fat reduction at 52 weeks was –3.9 percentage points for exercise plus liraglutide as compared with placebo, or roughly twice the reductions seen in the exercise- and liraglutide-alone groups, the investigators said, adding that the combination preserved lean mass.

Reductions in hemoglobin A1c, which are generally thought to reduce diabetes risk, were reduced in both the liraglutide and liraglutide-exercise combination group, according to their report.

The research was supported in part by grants from the Novo Nordisk Foundation.

For persons with obesity who lost a substantial amount of weight on a low-calorie diet, the combination of exercise and medication significantly improved weight-loss maintenance, and more so than either strategy alone, according to results of a randomized, head-to-head trial.

A year after starting moderate to vigorous exercise coupled with liraglutide treatment, study participants had a weight loss 9.5 kg more than those who received placebo and usual activity, study results show.

Reductions in both weight and fat loss seen with exercise and liraglutide was roughly twice as much as what was achieved at 1 year with the strategies of liraglutide or exercise alone, according to authors of the study, which appears in the New England Journal of Medicine .

Although the findings may not apply to those who can’t or won’t perform moderate to vigorous exercise, the intervention in this study was nevertheless feasible in this group of persons with obesity who had a very low level of fitness, according to the authors.
 

Hope for healthy weight loss maintenance

Investigator Signe S. Torekov, PhD, said in an interview that these results provide hope that more-intensive exercise regimens, with or without medication, can be useful and well accepted among individuals struggling with obesity.

“When we started our study, we were told, ‘you are never going to have people with obesity exercising that much, and for that long’ – but people were actually very happy about the exercise,” said Dr. Torekov, a professor in the department of biomedical sciences at the University of Copenhagen.

“If you actually set up a program where people are monitored and you have a feedback system, then exercise is an excellent component in obesity treatment that should be much more actively used – not only for its weight-lowering component, but also for improving health and quality of life,” she said in an interview.

Weight-management specialist John D. Clark, MD, PhD, said results of this study can be used to help inform patients about how successful different strategies incorporating exercise and medication may be following initial weight loss.

“When patients plateau on a consistent, calorie-restricted dietary plan, we can educate them and manage expectations about what options may be available to them after their initial weight loss,” said Dr. Clark, of the University of Texas, Dallas.

“If the patient’s goal specifically is weight loss at all costs, then I may suggest, ‘let’s consider liraglutide or liraglutide in combination with exercise,’ ” he said in an interview. “Exercise improves body composition, even if it may not on its own be as successful in the next phase of their weight-loss journey, as shown in this study.”
 

Obesity and weight-loss challenges

Although it’s not uncommon for obese patients to lose a large amount of weight, keeping the weight off is frequently a challenge unless the patient follows a structured weight maintenance program, according to Dr. Torekov and coauthors.

The rapid weight regain seen in many obese patients could be a result of reductions in total energy expenditure or increased appetite. Exercise is one strategy to sustain weight loss, though according to the authors, very few studies have looked at exercise in isolation to quantify its contribution to maintenance.

Accordingly, the present study sought to determine whether exercise, medication, or the combination thereof works best to keep weight off.

The study incorporated liraglutide, a GLP-1 receptor agonist indicated for chronic weight management, along with a reduced-calorie diet and increased physical activity, in adults with elevated body mass index and at least one weight-related comorbidity.

The investigator-initiated phase 3 trial included 215 adults with a body mass index of 32-43. Individuals with type 2 diabetes were excluded. All participants followed an 8-week, low-calorie diet comprising 800 calories per day.

Participants who lost 5% or more of their body weight were then randomized to 1 year of exercise plus liraglutide, exercise plus placebo, usual activity plus liraglutide, or usual activity plus placebo.

The exercise program – which was structured but flexible, according to investigators – included group exercise sessions that incorporated 30 minutes of indoor cycling and 15 minutes of circuit training 2 days each week. Participants wore heart rate monitors during exercise to make sure they reached targets for moderate to vigorous intensity.

Instructors trained in exercise physiology planned and monitored individualized exercise programs for each participant in the exercise-medication or exercise-only arms of the study.

Participants in all groups attended 12 one-on-one consultations where body weight was measured and dietetic support was provided.
 

Weight loss with exercise and medication

Out of 215 individuals enrolled in the study, 195 lost at least 5% of body weight and continued on to the randomized portion, the investigators reported. During the diet phase, they lost a mean of 13.1 kg, translating into a 12% mean reduction in body weight.

The mean frequency of exercise was 2.4 times per week in the exercise-plus-medication group and 2.5 times per week in the exercise-only group. About one-third of the exercise took place in the group sessions, and there was no difference in relative intensity between group and individual exercise regimens, the investigators said.

Individuals in the exercise plus medication group continued to lose more weight, such that, at the end of 1 year, the weight loss decreased even further, by a mean of –3.4 kg. By contrast, weight increased by a mean of 6.1 kg for the placebo group, adding up to a treatment difference of –9.5 kg (95% confidence interval, –13.1 to –5.9; P < .001), according to the report.

That treatment effect was also seen, but more muted, in the exercise- and liraglutide-only groups, at –4.1 kg and –6.8 kg, respectively.

A significant treatment effect was observed for exercise plus liraglutide, compared with exercise alone, at –5.4 kg (P = .004), while the treatment effect for the combination versus liraglutide alone was not significant at –2.7 kg (P = .13), the data show.

Body-fat reduction at 52 weeks was –3.9 percentage points for exercise plus liraglutide as compared with placebo, or roughly twice the reductions seen in the exercise- and liraglutide-alone groups, the investigators said, adding that the combination preserved lean mass.

Reductions in hemoglobin A1c, which are generally thought to reduce diabetes risk, were reduced in both the liraglutide and liraglutide-exercise combination group, according to their report.

The research was supported in part by grants from the Novo Nordisk Foundation.

For persons with obesity who lost a substantial amount of weight on a low-calorie diet, the combination of exercise and medication significantly improved weight-loss maintenance, and more so than either strategy alone, according to results of a randomized, head-to-head trial.

A year after starting moderate to vigorous exercise coupled with liraglutide treatment, study participants had a weight loss 9.5 kg more than those who received placebo and usual activity, study results show.

Reductions in both weight and fat loss seen with exercise and liraglutide was roughly twice as much as what was achieved at 1 year with the strategies of liraglutide or exercise alone, according to authors of the study, which appears in the New England Journal of Medicine .

Although the findings may not apply to those who can’t or won’t perform moderate to vigorous exercise, the intervention in this study was nevertheless feasible in this group of persons with obesity who had a very low level of fitness, according to the authors.
 

Hope for healthy weight loss maintenance

Investigator Signe S. Torekov, PhD, said in an interview that these results provide hope that more-intensive exercise regimens, with or without medication, can be useful and well accepted among individuals struggling with obesity.

“When we started our study, we were told, ‘you are never going to have people with obesity exercising that much, and for that long’ – but people were actually very happy about the exercise,” said Dr. Torekov, a professor in the department of biomedical sciences at the University of Copenhagen.

“If you actually set up a program where people are monitored and you have a feedback system, then exercise is an excellent component in obesity treatment that should be much more actively used – not only for its weight-lowering component, but also for improving health and quality of life,” she said in an interview.

Weight-management specialist John D. Clark, MD, PhD, said results of this study can be used to help inform patients about how successful different strategies incorporating exercise and medication may be following initial weight loss.

“When patients plateau on a consistent, calorie-restricted dietary plan, we can educate them and manage expectations about what options may be available to them after their initial weight loss,” said Dr. Clark, of the University of Texas, Dallas.

“If the patient’s goal specifically is weight loss at all costs, then I may suggest, ‘let’s consider liraglutide or liraglutide in combination with exercise,’ ” he said in an interview. “Exercise improves body composition, even if it may not on its own be as successful in the next phase of their weight-loss journey, as shown in this study.”
 

Obesity and weight-loss challenges

Although it’s not uncommon for obese patients to lose a large amount of weight, keeping the weight off is frequently a challenge unless the patient follows a structured weight maintenance program, according to Dr. Torekov and coauthors.

The rapid weight regain seen in many obese patients could be a result of reductions in total energy expenditure or increased appetite. Exercise is one strategy to sustain weight loss, though according to the authors, very few studies have looked at exercise in isolation to quantify its contribution to maintenance.

Accordingly, the present study sought to determine whether exercise, medication, or the combination thereof works best to keep weight off.

The study incorporated liraglutide, a GLP-1 receptor agonist indicated for chronic weight management, along with a reduced-calorie diet and increased physical activity, in adults with elevated body mass index and at least one weight-related comorbidity.

The investigator-initiated phase 3 trial included 215 adults with a body mass index of 32-43. Individuals with type 2 diabetes were excluded. All participants followed an 8-week, low-calorie diet comprising 800 calories per day.

Participants who lost 5% or more of their body weight were then randomized to 1 year of exercise plus liraglutide, exercise plus placebo, usual activity plus liraglutide, or usual activity plus placebo.

The exercise program – which was structured but flexible, according to investigators – included group exercise sessions that incorporated 30 minutes of indoor cycling and 15 minutes of circuit training 2 days each week. Participants wore heart rate monitors during exercise to make sure they reached targets for moderate to vigorous intensity.

Instructors trained in exercise physiology planned and monitored individualized exercise programs for each participant in the exercise-medication or exercise-only arms of the study.

Participants in all groups attended 12 one-on-one consultations where body weight was measured and dietetic support was provided.
 

Weight loss with exercise and medication

Out of 215 individuals enrolled in the study, 195 lost at least 5% of body weight and continued on to the randomized portion, the investigators reported. During the diet phase, they lost a mean of 13.1 kg, translating into a 12% mean reduction in body weight.

The mean frequency of exercise was 2.4 times per week in the exercise-plus-medication group and 2.5 times per week in the exercise-only group. About one-third of the exercise took place in the group sessions, and there was no difference in relative intensity between group and individual exercise regimens, the investigators said.

Individuals in the exercise plus medication group continued to lose more weight, such that, at the end of 1 year, the weight loss decreased even further, by a mean of –3.4 kg. By contrast, weight increased by a mean of 6.1 kg for the placebo group, adding up to a treatment difference of –9.5 kg (95% confidence interval, –13.1 to –5.9; P < .001), according to the report.

That treatment effect was also seen, but more muted, in the exercise- and liraglutide-only groups, at –4.1 kg and –6.8 kg, respectively.

A significant treatment effect was observed for exercise plus liraglutide, compared with exercise alone, at –5.4 kg (P = .004), while the treatment effect for the combination versus liraglutide alone was not significant at –2.7 kg (P = .13), the data show.

Body-fat reduction at 52 weeks was –3.9 percentage points for exercise plus liraglutide as compared with placebo, or roughly twice the reductions seen in the exercise- and liraglutide-alone groups, the investigators said, adding that the combination preserved lean mass.

Reductions in hemoglobin A1c, which are generally thought to reduce diabetes risk, were reduced in both the liraglutide and liraglutide-exercise combination group, according to their report.

The research was supported in part by grants from the Novo Nordisk Foundation.

Nonalcoholic fatty liver disease (NAFLD) was present in approximately two-thirds of patients who did not undergo a liver biopsy. These patients were more likely to be non-White and older, as well as have normal ALT levels, which shows potential gaps in knowledge about this population.

Shidlovski/Getty Images

Data from studies of patients diagnosed with NAFLD that require biopsy among their inclusion criteria may be subject to selection and detection bias, wrote A. Sidney Barritt, MD, of the University of North Carolina at Chapel Hill, and colleagues. The researchers sought to compare characteristics of patients with NAFLD who were diagnosed using clinical criteria and those diagnosed via liver biopsy.

In a study published in Hepatology Communications, the researchers reviewed data from TARGET-NASH, a longitudinal, observational cohort study designed to follow patients with NAFLD in clinical practice to provide data on the effectiveness of treatments.

“TARGET-NASH represents a large cohort of NAFLD patients from multiple sites and can provide us with real world information on progression of disease in patients with NAFLD and particular risk factors that may be clinically relevant,” Zachary Henry, MD, MS, of the division of gastroenterology & hepatology at the University of Virginia Health System in Charlottesville, said in an interview. “This is one of the first studies from this database, and as time goes on, we will see more large-population data like this to answer specific questions for NAFLD patient.”
 

Surprising findings

The researchers included 3,474 patients aged 18 years and older who were enrolled in the TARGET-NASH study between Aug. 1, 2016, and March 4, 2019. The study participants were classified according to severity of liver disease: nonalcoholic fatty liver (30%), nonalcoholic steatohepatitis (37%), and NAFLD cirrhosis (33%).

A total of 766 patients were diagnosed with NASH based on clinical criteria without biopsy, and all met the criteria for abnormal ALT and steatosis based on imaging. In addition, these patients had at least one secondary diagnostic criteria: body mass index greater than 30 kg/m2 (74%), type 2 diabetes (42%), and dyslipidemia (54%). Significant independent predictors of liver biopsy included younger age, White race, female gender, diabetes, and elevated levels of ALT.

Elevated ALT increased the odds of liver biopsy by 14% per 10-point rise, according to the study. A machine learning model showed that non-White patients with ALT less than 69 IU/mL had a 6% chance of liver biopsy. By comparison, White patients had a 21% chance of biopsy with ALT between 29 IU/mL and 69 IU/mL that dropped to 10% if the ALT was less than 29 IU/mL.

However, ALT remains a “suboptimal surrogate” for disease severity, the researchers noted. “How a normal ALT is defined and how a normal ALT range may vary across different laboratories may play a role in its utility as a diagnostic tool as well.”

Dr. Henry was surprised by this finding: “With the advent of noninvasive measures of fibrosis, such as the NAFLD fibrosis score, Fibrosis-4, and transient elastography, I thought these would have a more significant role in that decision as opposed to ALT levels.”

Notably, mental health diagnoses accounted for nearly half (49%) of comorbid conditions, followed by cardiovascular disease (19%), and osteoarthritis (10%). The prevalence of these conditions emphasizes the challenges of managing patients with NAFLD with diet and exercise alone because mental and physical problems may impede progress, the researchers wrote.

The study findings were limited by several factors including the inability to determine health care provider intent, as well as undocumented factors related to patients and providers that might influence a biopsy decision, such as assessment of disease severity, the researchers noted. In addition, they noted that the mostly White study population treated in specialty settings might not generalize to other populations or primary care.

However, the findings are strengthened by the large study population and real-world setting, the researchers emphasized. “These data provide context for the selection bias that may be present in many registries and randomized, controlled trials of therapies for NAFLD, where biopsy is required for inclusion,” and show potential knowledge gaps about the patient population less likely to undergo biopsy.
 

Knowledge gaps and implications

The study is important because of the need to identify patient factors that predict histologic versus clinical diagnosis of NAFLD as the number of patient registries and clinical trials for NAFLD increase, Bubu Banini, MD, of Yale University, New Haven, Conn., said in an interview. “This information helps to elucidate selection and ascertainment bias and place findings from NAFLD registries and clinical trials into context.”

Dr. Banini said that some of the findings were to be expected, while others were not.

“Historically, males and non-Whites are less likely to participate in registries and clinical trials, compared to females and Whites. However, I was surprised to find that these discrepancies further paralleled the likelihood of undergoing liver biopsy even among those who chose to participate. In addition, while mental health disorders (such as anxiety and depression) are a fairly prevalent comorbidity in patients with NAFLD, I was surprised to find that NAFLD patients with mental health disorders were more likely to undergo liver biopsy compared to those without these disorders. I would have expected the reverse,” he noted.

“These findings highlight the gaps in knowledge regarding the impact of demographic and psychosocial factors on choice and assess to care among patients with NAFLD, and the need for further studies to address these gaps,” she emphasized.

“A number of [studies] such as TARGET-NASH are doing away with the requirement for liver biopsy for participation; hence, it is less likely that selection bias related to liver biopsy would be a problem in these [studies] if clinical diagnosis is considered as a surrogate for histological diagnosis,” Dr. Banini added.

“On the contrary, many NAFLD clinical trials require liver biopsy for inclusion.” As nicely demonstrated in the current study, “this inclusion criterion may introduce selection bias,” she said. “Awareness of potential biases would hopefully inform the design and recruitment strategy for registries and clinical trials in order to overcome these issues.”

“I think the results of this study may actually point to a larger issue within medicine in general, which is a difference in care provided to minority communities,” Dr. Henry said. “Whether this is intentional, related to unconscious bias on the part of providers, or related to a significant mistrust between minority communities and their health care providers is unclear but certainly needs to be addressed.”

He noted that the purpose of TARGET-NASH is to enroll all patients with NAFLD regardless of biopsy. “Over time, as we have more data on these patients, we will have a better understanding of both diagnostic and therapeutic decisions in patients with NAFLD.”

The study was supported by Target RWE, sponsor of the TARGET-NASH study. TARGET-NASH is a collaboration of academic and community investigators and the pharmaceutical industry. Lead author Dr. Barritt had no financial conflicts to disclose, but many study coauthors disclosed relationships with multiple pharmaceutical companies, including those involved in the TARGET-NASH study. Dr. Banini currently serves on the NASH advisory board for Boehringer Ingelheim. Dr. Henry reported no disclosures, although his institution is one of the enrollment sites for TARGET-NASH.

Nonalcoholic fatty liver disease (NAFLD) was present in approximately two-thirds of patients who did not undergo a liver biopsy. These patients were more likely to be non-White and older, as well as have normal ALT levels, which shows potential gaps in knowledge about this population.

Shidlovski/Getty Images

Data from studies of patients diagnosed with NAFLD that require biopsy among their inclusion criteria may be subject to selection and detection bias, wrote A. Sidney Barritt, MD, of the University of North Carolina at Chapel Hill, and colleagues. The researchers sought to compare characteristics of patients with NAFLD who were diagnosed using clinical criteria and those diagnosed via liver biopsy.

In a study published in Hepatology Communications, the researchers reviewed data from TARGET-NASH, a longitudinal, observational cohort study designed to follow patients with NAFLD in clinical practice to provide data on the effectiveness of treatments.

“TARGET-NASH represents a large cohort of NAFLD patients from multiple sites and can provide us with real world information on progression of disease in patients with NAFLD and particular risk factors that may be clinically relevant,” Zachary Henry, MD, MS, of the division of gastroenterology & hepatology at the University of Virginia Health System in Charlottesville, said in an interview. “This is one of the first studies from this database, and as time goes on, we will see more large-population data like this to answer specific questions for NAFLD patient.”
 

Surprising findings

The researchers included 3,474 patients aged 18 years and older who were enrolled in the TARGET-NASH study between Aug. 1, 2016, and March 4, 2019. The study participants were classified according to severity of liver disease: nonalcoholic fatty liver (30%), nonalcoholic steatohepatitis (37%), and NAFLD cirrhosis (33%).

A total of 766 patients were diagnosed with NASH based on clinical criteria without biopsy, and all met the criteria for abnormal ALT and steatosis based on imaging. In addition, these patients had at least one secondary diagnostic criteria: body mass index greater than 30 kg/m2 (74%), type 2 diabetes (42%), and dyslipidemia (54%). Significant independent predictors of liver biopsy included younger age, White race, female gender, diabetes, and elevated levels of ALT.

Elevated ALT increased the odds of liver biopsy by 14% per 10-point rise, according to the study. A machine learning model showed that non-White patients with ALT less than 69 IU/mL had a 6% chance of liver biopsy. By comparison, White patients had a 21% chance of biopsy with ALT between 29 IU/mL and 69 IU/mL that dropped to 10% if the ALT was less than 29 IU/mL.

However, ALT remains a “suboptimal surrogate” for disease severity, the researchers noted. “How a normal ALT is defined and how a normal ALT range may vary across different laboratories may play a role in its utility as a diagnostic tool as well.”

Dr. Henry was surprised by this finding: “With the advent of noninvasive measures of fibrosis, such as the NAFLD fibrosis score, Fibrosis-4, and transient elastography, I thought these would have a more significant role in that decision as opposed to ALT levels.”

Notably, mental health diagnoses accounted for nearly half (49%) of comorbid conditions, followed by cardiovascular disease (19%), and osteoarthritis (10%). The prevalence of these conditions emphasizes the challenges of managing patients with NAFLD with diet and exercise alone because mental and physical problems may impede progress, the researchers wrote.

The study findings were limited by several factors including the inability to determine health care provider intent, as well as undocumented factors related to patients and providers that might influence a biopsy decision, such as assessment of disease severity, the researchers noted. In addition, they noted that the mostly White study population treated in specialty settings might not generalize to other populations or primary care.

However, the findings are strengthened by the large study population and real-world setting, the researchers emphasized. “These data provide context for the selection bias that may be present in many registries and randomized, controlled trials of therapies for NAFLD, where biopsy is required for inclusion,” and show potential knowledge gaps about the patient population less likely to undergo biopsy.
 

Knowledge gaps and implications

The study is important because of the need to identify patient factors that predict histologic versus clinical diagnosis of NAFLD as the number of patient registries and clinical trials for NAFLD increase, Bubu Banini, MD, of Yale University, New Haven, Conn., said in an interview. “This information helps to elucidate selection and ascertainment bias and place findings from NAFLD registries and clinical trials into context.”

Dr. Banini said that some of the findings were to be expected, while others were not.

“Historically, males and non-Whites are less likely to participate in registries and clinical trials, compared to females and Whites. However, I was surprised to find that these discrepancies further paralleled the likelihood of undergoing liver biopsy even among those who chose to participate. In addition, while mental health disorders (such as anxiety and depression) are a fairly prevalent comorbidity in patients with NAFLD, I was surprised to find that NAFLD patients with mental health disorders were more likely to undergo liver biopsy compared to those without these disorders. I would have expected the reverse,” he noted.

“These findings highlight the gaps in knowledge regarding the impact of demographic and psychosocial factors on choice and assess to care among patients with NAFLD, and the need for further studies to address these gaps,” she emphasized.

“A number of [studies] such as TARGET-NASH are doing away with the requirement for liver biopsy for participation; hence, it is less likely that selection bias related to liver biopsy would be a problem in these [studies] if clinical diagnosis is considered as a surrogate for histological diagnosis,” Dr. Banini added.

“On the contrary, many NAFLD clinical trials require liver biopsy for inclusion.” As nicely demonstrated in the current study, “this inclusion criterion may introduce selection bias,” she said. “Awareness of potential biases would hopefully inform the design and recruitment strategy for registries and clinical trials in order to overcome these issues.”

“I think the results of this study may actually point to a larger issue within medicine in general, which is a difference in care provided to minority communities,” Dr. Henry said. “Whether this is intentional, related to unconscious bias on the part of providers, or related to a significant mistrust between minority communities and their health care providers is unclear but certainly needs to be addressed.”

He noted that the purpose of TARGET-NASH is to enroll all patients with NAFLD regardless of biopsy. “Over time, as we have more data on these patients, we will have a better understanding of both diagnostic and therapeutic decisions in patients with NAFLD.”

The study was supported by Target RWE, sponsor of the TARGET-NASH study. TARGET-NASH is a collaboration of academic and community investigators and the pharmaceutical industry. Lead author Dr. Barritt had no financial conflicts to disclose, but many study coauthors disclosed relationships with multiple pharmaceutical companies, including those involved in the TARGET-NASH study. Dr. Banini currently serves on the NASH advisory board for Boehringer Ingelheim. Dr. Henry reported no disclosures, although his institution is one of the enrollment sites for TARGET-NASH.

Nonalcoholic fatty liver disease (NAFLD) was present in approximately two-thirds of patients who did not undergo a liver biopsy. These patients were more likely to be non-White and older, as well as have normal ALT levels, which shows potential gaps in knowledge about this population.

Shidlovski/Getty Images

Data from studies of patients diagnosed with NAFLD that require biopsy among their inclusion criteria may be subject to selection and detection bias, wrote A. Sidney Barritt, MD, of the University of North Carolina at Chapel Hill, and colleagues. The researchers sought to compare characteristics of patients with NAFLD who were diagnosed using clinical criteria and those diagnosed via liver biopsy.

In a study published in Hepatology Communications, the researchers reviewed data from TARGET-NASH, a longitudinal, observational cohort study designed to follow patients with NAFLD in clinical practice to provide data on the effectiveness of treatments.

“TARGET-NASH represents a large cohort of NAFLD patients from multiple sites and can provide us with real world information on progression of disease in patients with NAFLD and particular risk factors that may be clinically relevant,” Zachary Henry, MD, MS, of the division of gastroenterology & hepatology at the University of Virginia Health System in Charlottesville, said in an interview. “This is one of the first studies from this database, and as time goes on, we will see more large-population data like this to answer specific questions for NAFLD patient.”
 

Surprising findings

The researchers included 3,474 patients aged 18 years and older who were enrolled in the TARGET-NASH study between Aug. 1, 2016, and March 4, 2019. The study participants were classified according to severity of liver disease: nonalcoholic fatty liver (30%), nonalcoholic steatohepatitis (37%), and NAFLD cirrhosis (33%).

A total of 766 patients were diagnosed with NASH based on clinical criteria without biopsy, and all met the criteria for abnormal ALT and steatosis based on imaging. In addition, these patients had at least one secondary diagnostic criteria: body mass index greater than 30 kg/m2 (74%), type 2 diabetes (42%), and dyslipidemia (54%). Significant independent predictors of liver biopsy included younger age, White race, female gender, diabetes, and elevated levels of ALT.

Elevated ALT increased the odds of liver biopsy by 14% per 10-point rise, according to the study. A machine learning model showed that non-White patients with ALT less than 69 IU/mL had a 6% chance of liver biopsy. By comparison, White patients had a 21% chance of biopsy with ALT between 29 IU/mL and 69 IU/mL that dropped to 10% if the ALT was less than 29 IU/mL.

However, ALT remains a “suboptimal surrogate” for disease severity, the researchers noted. “How a normal ALT is defined and how a normal ALT range may vary across different laboratories may play a role in its utility as a diagnostic tool as well.”

Dr. Henry was surprised by this finding: “With the advent of noninvasive measures of fibrosis, such as the NAFLD fibrosis score, Fibrosis-4, and transient elastography, I thought these would have a more significant role in that decision as opposed to ALT levels.”

Notably, mental health diagnoses accounted for nearly half (49%) of comorbid conditions, followed by cardiovascular disease (19%), and osteoarthritis (10%). The prevalence of these conditions emphasizes the challenges of managing patients with NAFLD with diet and exercise alone because mental and physical problems may impede progress, the researchers wrote.

The study findings were limited by several factors including the inability to determine health care provider intent, as well as undocumented factors related to patients and providers that might influence a biopsy decision, such as assessment of disease severity, the researchers noted. In addition, they noted that the mostly White study population treated in specialty settings might not generalize to other populations or primary care.

However, the findings are strengthened by the large study population and real-world setting, the researchers emphasized. “These data provide context for the selection bias that may be present in many registries and randomized, controlled trials of therapies for NAFLD, where biopsy is required for inclusion,” and show potential knowledge gaps about the patient population less likely to undergo biopsy.
 

Knowledge gaps and implications

The study is important because of the need to identify patient factors that predict histologic versus clinical diagnosis of NAFLD as the number of patient registries and clinical trials for NAFLD increase, Bubu Banini, MD, of Yale University, New Haven, Conn., said in an interview. “This information helps to elucidate selection and ascertainment bias and place findings from NAFLD registries and clinical trials into context.”

Dr. Banini said that some of the findings were to be expected, while others were not.

“Historically, males and non-Whites are less likely to participate in registries and clinical trials, compared to females and Whites. However, I was surprised to find that these discrepancies further paralleled the likelihood of undergoing liver biopsy even among those who chose to participate. In addition, while mental health disorders (such as anxiety and depression) are a fairly prevalent comorbidity in patients with NAFLD, I was surprised to find that NAFLD patients with mental health disorders were more likely to undergo liver biopsy compared to those without these disorders. I would have expected the reverse,” he noted.

“These findings highlight the gaps in knowledge regarding the impact of demographic and psychosocial factors on choice and assess to care among patients with NAFLD, and the need for further studies to address these gaps,” she emphasized.

“A number of [studies] such as TARGET-NASH are doing away with the requirement for liver biopsy for participation; hence, it is less likely that selection bias related to liver biopsy would be a problem in these [studies] if clinical diagnosis is considered as a surrogate for histological diagnosis,” Dr. Banini added.

“On the contrary, many NAFLD clinical trials require liver biopsy for inclusion.” As nicely demonstrated in the current study, “this inclusion criterion may introduce selection bias,” she said. “Awareness of potential biases would hopefully inform the design and recruitment strategy for registries and clinical trials in order to overcome these issues.”

“I think the results of this study may actually point to a larger issue within medicine in general, which is a difference in care provided to minority communities,” Dr. Henry said. “Whether this is intentional, related to unconscious bias on the part of providers, or related to a significant mistrust between minority communities and their health care providers is unclear but certainly needs to be addressed.”

He noted that the purpose of TARGET-NASH is to enroll all patients with NAFLD regardless of biopsy. “Over time, as we have more data on these patients, we will have a better understanding of both diagnostic and therapeutic decisions in patients with NAFLD.”

The study was supported by Target RWE, sponsor of the TARGET-NASH study. TARGET-NASH is a collaboration of academic and community investigators and the pharmaceutical industry. Lead author Dr. Barritt had no financial conflicts to disclose, but many study coauthors disclosed relationships with multiple pharmaceutical companies, including those involved in the TARGET-NASH study. Dr. Banini currently serves on the NASH advisory board for Boehringer Ingelheim. Dr. Henry reported no disclosures, although his institution is one of the enrollment sites for TARGET-NASH.

The risk of severe outcomes with COVID-19 increases with excess weight in a linear manner beginning in normal body mass index ranges, with the effect apparently independent of obesity-related diseases such as diabetes, and stronger among younger people and Black persons, new research shows.

“Even a small increase in body mass index above 23 kg/m² is a risk factor for adverse outcomes after infection with SARS-CoV-2,” the authors reported.

“Excess weight is a modifiable risk factor and investment in the treatment of overweight and obesity, and long-term preventive strategies could help reduce the severity of COVID-19 disease,” they wrote.

The findings shed important new light in the ongoing efforts to understand COVID-19 effects, Krishnan Bhaskaran, PhD, said in an interview.

“These results confirm and add detail to the established links between overweight and obesity and COVID-19, and also add new information on risks among people with low BMI levels,” said Dr. Bhaskaran, an epidemiologist at the London School of Hygiene & Tropical Medicine, who authored an accompanying editorial (Lancet Diabetes Endocrinol 2021 Apr 29; doi: 10.1016/S2213-8587[21]00109-1).

Obesity has been well established as a major risk factor for poor outcomes among people with COVID-19; however, less is known about the risk of severe outcomes over the broader spectrum of excess weight, and its relationship with other factors.

For the prospective, community-based study, Carmen Piernas, PhD, of the University of Oxford (England) and colleagues evaluated data on nearly 7 million individuals registered in the U.K. QResearch database during Jan. 24–April 30, 2020.

Overall, patients had a mean BMI of 27 kg/m². Among them, 13,503 (.20%) were admitted to the hospital during the study period, 1,601 (.02%) were admitted to an ICU and 5,479 (.08%) died after testing positive for SARS-CoV-2.


 

Risk rises from BMI of 23 kg/m²

In looking at the risk of hospital admission with COVID-19, the authors found a J-shaped relationship with BMI, with the risk increased with a BMI of 20 kg/m² or lower, as well as an increased risk beginning with a BMI of 23 kg/m² – considered normal weight – or higher (hazard ratio, 1.05).

The risk of death from COVID-19 was also J-shaped, however the association with increases in BMI started higher – at 28 kg/m² (adjusted HR 1.04).

In terms of the risk of ICU admission with COVID-19, the curve was not J-shaped, with just a linear association of admission with increasing BMI beginning at 23 kg/m² (adjusted HR 1.10).

“It was surprising to see that the lowest risk of severe COVID-19 was found at a BMI of 23, and each extra BMI unit was associated with significantly higher risk, but we don’t really know yet what the reason is for this,” Dr. Piernas said in an interview.

The association between increasing BMI and risk of hospital admission for COVID-19 beginning at a BMI of 23 kg/m² was more significant among younger people aged 20-39 years than in those aged 80-100 years, with an adjusted HR for hospital admission per BMI unit above 23 kg/m² of 1.09 versus 1.01 (P < .0001).

In addition, the risk associated with BMI and hospital admission was stronger in people who were Black, compared with those who were White (1.07 vs. 1.04), as was the risk of death due to COVID-19 (1.08 vs. 1.04; P < .0001 for both).

“For the risk of death, Blacks have an 8% higher risk with each extra BMI unit, whereas Whites have a 4% increase, which is half the risk,” Dr. Piernas said.

Notably, the increased risks of hospital admission and ICU due to COVID-19 seen with increases in BMI were slightly lower among people with type 2 diabetes, hypertension, and cardiovascular disease compared with patients who did not have those comorbidities, suggesting the association with BMI is not explained by those risk factors.

Dr. Piernas speculated that the effect could reflect that people with diabetes or cardiovascular disease already have a preexisting condition which makes them more susceptible to SARS-CoV-2.

Hence, “the association with BMI in this group may not be as strong as the association found among those without those conditions, in which BMI explains a higher proportion of this increased risk, given the absence of these preexisting conditions.”

Similarly, the effect of BMI on COVID-19 outcomes in younger patients may appear stronger because their rates of other comorbidities are much lower than in older patients.

“Among older people, preexisting conditions and perhaps a weaker immune system may explain their much higher rates of severe COVID outcomes,” Dr. Piernas noted.

Furthermore, older patients may have frailty and high comorbidities that could explain their lower rates of ICU admission with COVID-19, Dr. Bhaskaran added in further comments.

The findings overall underscore that excess weight can represent a risk in COVID-19 outcomes that is, importantly, modifiable, and “suggest that supporting people to reach and maintain a healthy weight is likely to help people reduce their risk of experiencing severe outcomes from this disease, now or in any future waves,” he concluded.

Dr. Piernas and Dr. Bhaskaran had no disclosures to report. Coauthors’ disclosures are detailed in the published study.

The risk of severe outcomes with COVID-19 increases with excess weight in a linear manner beginning in normal body mass index ranges, with the effect apparently independent of obesity-related diseases such as diabetes, and stronger among younger people and Black persons, new research shows.

“Even a small increase in body mass index above 23 kg/m² is a risk factor for adverse outcomes after infection with SARS-CoV-2,” the authors reported.

“Excess weight is a modifiable risk factor and investment in the treatment of overweight and obesity, and long-term preventive strategies could help reduce the severity of COVID-19 disease,” they wrote.

The findings shed important new light in the ongoing efforts to understand COVID-19 effects, Krishnan Bhaskaran, PhD, said in an interview.

“These results confirm and add detail to the established links between overweight and obesity and COVID-19, and also add new information on risks among people with low BMI levels,” said Dr. Bhaskaran, an epidemiologist at the London School of Hygiene & Tropical Medicine, who authored an accompanying editorial (Lancet Diabetes Endocrinol 2021 Apr 29; doi: 10.1016/S2213-8587[21]00109-1).

Obesity has been well established as a major risk factor for poor outcomes among people with COVID-19; however, less is known about the risk of severe outcomes over the broader spectrum of excess weight, and its relationship with other factors.

For the prospective, community-based study, Carmen Piernas, PhD, of the University of Oxford (England) and colleagues evaluated data on nearly 7 million individuals registered in the U.K. QResearch database during Jan. 24–April 30, 2020.

Overall, patients had a mean BMI of 27 kg/m². Among them, 13,503 (.20%) were admitted to the hospital during the study period, 1,601 (.02%) were admitted to an ICU and 5,479 (.08%) died after testing positive for SARS-CoV-2.


 

Risk rises from BMI of 23 kg/m²

In looking at the risk of hospital admission with COVID-19, the authors found a J-shaped relationship with BMI, with the risk increased with a BMI of 20 kg/m² or lower, as well as an increased risk beginning with a BMI of 23 kg/m² – considered normal weight – or higher (hazard ratio, 1.05).

The risk of death from COVID-19 was also J-shaped, however the association with increases in BMI started higher – at 28 kg/m² (adjusted HR 1.04).

In terms of the risk of ICU admission with COVID-19, the curve was not J-shaped, with just a linear association of admission with increasing BMI beginning at 23 kg/m² (adjusted HR 1.10).

“It was surprising to see that the lowest risk of severe COVID-19 was found at a BMI of 23, and each extra BMI unit was associated with significantly higher risk, but we don’t really know yet what the reason is for this,” Dr. Piernas said in an interview.

The association between increasing BMI and risk of hospital admission for COVID-19 beginning at a BMI of 23 kg/m² was more significant among younger people aged 20-39 years than in those aged 80-100 years, with an adjusted HR for hospital admission per BMI unit above 23 kg/m² of 1.09 versus 1.01 (P < .0001).

In addition, the risk associated with BMI and hospital admission was stronger in people who were Black, compared with those who were White (1.07 vs. 1.04), as was the risk of death due to COVID-19 (1.08 vs. 1.04; P < .0001 for both).

“For the risk of death, Blacks have an 8% higher risk with each extra BMI unit, whereas Whites have a 4% increase, which is half the risk,” Dr. Piernas said.

Notably, the increased risks of hospital admission and ICU due to COVID-19 seen with increases in BMI were slightly lower among people with type 2 diabetes, hypertension, and cardiovascular disease compared with patients who did not have those comorbidities, suggesting the association with BMI is not explained by those risk factors.

Dr. Piernas speculated that the effect could reflect that people with diabetes or cardiovascular disease already have a preexisting condition which makes them more susceptible to SARS-CoV-2.

Hence, “the association with BMI in this group may not be as strong as the association found among those without those conditions, in which BMI explains a higher proportion of this increased risk, given the absence of these preexisting conditions.”

Similarly, the effect of BMI on COVID-19 outcomes in younger patients may appear stronger because their rates of other comorbidities are much lower than in older patients.

“Among older people, preexisting conditions and perhaps a weaker immune system may explain their much higher rates of severe COVID outcomes,” Dr. Piernas noted.

Furthermore, older patients may have frailty and high comorbidities that could explain their lower rates of ICU admission with COVID-19, Dr. Bhaskaran added in further comments.

The findings overall underscore that excess weight can represent a risk in COVID-19 outcomes that is, importantly, modifiable, and “suggest that supporting people to reach and maintain a healthy weight is likely to help people reduce their risk of experiencing severe outcomes from this disease, now or in any future waves,” he concluded.

Dr. Piernas and Dr. Bhaskaran had no disclosures to report. Coauthors’ disclosures are detailed in the published study.

The risk of severe outcomes with COVID-19 increases with excess weight in a linear manner beginning in normal body mass index ranges, with the effect apparently independent of obesity-related diseases such as diabetes, and stronger among younger people and Black persons, new research shows.

“Even a small increase in body mass index above 23 kg/m² is a risk factor for adverse outcomes after infection with SARS-CoV-2,” the authors reported.

“Excess weight is a modifiable risk factor and investment in the treatment of overweight and obesity, and long-term preventive strategies could help reduce the severity of COVID-19 disease,” they wrote.

The findings shed important new light in the ongoing efforts to understand COVID-19 effects, Krishnan Bhaskaran, PhD, said in an interview.

“These results confirm and add detail to the established links between overweight and obesity and COVID-19, and also add new information on risks among people with low BMI levels,” said Dr. Bhaskaran, an epidemiologist at the London School of Hygiene & Tropical Medicine, who authored an accompanying editorial (Lancet Diabetes Endocrinol 2021 Apr 29; doi: 10.1016/S2213-8587[21]00109-1).

Obesity has been well established as a major risk factor for poor outcomes among people with COVID-19; however, less is known about the risk of severe outcomes over the broader spectrum of excess weight, and its relationship with other factors.

For the prospective, community-based study, Carmen Piernas, PhD, of the University of Oxford (England) and colleagues evaluated data on nearly 7 million individuals registered in the U.K. QResearch database during Jan. 24–April 30, 2020.

Overall, patients had a mean BMI of 27 kg/m². Among them, 13,503 (.20%) were admitted to the hospital during the study period, 1,601 (.02%) were admitted to an ICU and 5,479 (.08%) died after testing positive for SARS-CoV-2.


 

Risk rises from BMI of 23 kg/m²

In looking at the risk of hospital admission with COVID-19, the authors found a J-shaped relationship with BMI, with the risk increased with a BMI of 20 kg/m² or lower, as well as an increased risk beginning with a BMI of 23 kg/m² – considered normal weight – or higher (hazard ratio, 1.05).

The risk of death from COVID-19 was also J-shaped, however the association with increases in BMI started higher – at 28 kg/m² (adjusted HR 1.04).

In terms of the risk of ICU admission with COVID-19, the curve was not J-shaped, with just a linear association of admission with increasing BMI beginning at 23 kg/m² (adjusted HR 1.10).

“It was surprising to see that the lowest risk of severe COVID-19 was found at a BMI of 23, and each extra BMI unit was associated with significantly higher risk, but we don’t really know yet what the reason is for this,” Dr. Piernas said in an interview.

The association between increasing BMI and risk of hospital admission for COVID-19 beginning at a BMI of 23 kg/m² was more significant among younger people aged 20-39 years than in those aged 80-100 years, with an adjusted HR for hospital admission per BMI unit above 23 kg/m² of 1.09 versus 1.01 (P < .0001).

In addition, the risk associated with BMI and hospital admission was stronger in people who were Black, compared with those who were White (1.07 vs. 1.04), as was the risk of death due to COVID-19 (1.08 vs. 1.04; P < .0001 for both).

“For the risk of death, Blacks have an 8% higher risk with each extra BMI unit, whereas Whites have a 4% increase, which is half the risk,” Dr. Piernas said.

Notably, the increased risks of hospital admission and ICU due to COVID-19 seen with increases in BMI were slightly lower among people with type 2 diabetes, hypertension, and cardiovascular disease compared with patients who did not have those comorbidities, suggesting the association with BMI is not explained by those risk factors.

Dr. Piernas speculated that the effect could reflect that people with diabetes or cardiovascular disease already have a preexisting condition which makes them more susceptible to SARS-CoV-2.

Hence, “the association with BMI in this group may not be as strong as the association found among those without those conditions, in which BMI explains a higher proportion of this increased risk, given the absence of these preexisting conditions.”

Similarly, the effect of BMI on COVID-19 outcomes in younger patients may appear stronger because their rates of other comorbidities are much lower than in older patients.

“Among older people, preexisting conditions and perhaps a weaker immune system may explain their much higher rates of severe COVID outcomes,” Dr. Piernas noted.

Furthermore, older patients may have frailty and high comorbidities that could explain their lower rates of ICU admission with COVID-19, Dr. Bhaskaran added in further comments.

The findings overall underscore that excess weight can represent a risk in COVID-19 outcomes that is, importantly, modifiable, and “suggest that supporting people to reach and maintain a healthy weight is likely to help people reduce their risk of experiencing severe outcomes from this disease, now or in any future waves,” he concluded.

Dr. Piernas and Dr. Bhaskaran had no disclosures to report. Coauthors’ disclosures are detailed in the published study.