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‘Conservative’ USPSTF primary prevention statin guidance finalized
Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.
The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.
The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.
And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).
The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.
The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.
“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
‘Sensible and practical’
The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.
It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.
“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”
Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.
The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.
“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.
“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
Higher threshold for therapy
The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.
In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.
“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.
That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.
The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.
For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”
Dose intensity, adverse events
Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”
The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”
Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”
But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”
Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.
“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”
It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.
“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.
“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”
However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.
And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”
USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.
A version of this article first appeared on Medscape.com.
Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.
The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.
The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.
And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).
The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.
The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.
“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
‘Sensible and practical’
The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.
It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.
“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”
Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.
The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.
“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.
“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
Higher threshold for therapy
The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.
In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.
“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.
That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.
The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.
For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”
Dose intensity, adverse events
Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”
The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”
Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”
But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”
Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.
“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”
It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.
“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.
“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”
However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.
And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”
USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.
A version of this article first appeared on Medscape.com.
Questions about how to prescribe statins for primary prevention abound more than 3 decades after the drugs swept into clinical practice to become a first-line medical approach to cutting cardiovascular (CV) risk. Statin usage recommendations from different bodies can vary in ways both limited and fundamental, spurring the kind of debate that accompanies such a document newly issued by the United States Preventive Services Task Force.
The document, little changed from the draft guidance released for public comment in February, was published online Aug. 23 in JAMA and the USPSTF website. It replaces a similar document issued by the task force in 2016.
The guidance has much in common with, but also sharp differences from, the influential 2018 guidelines on blood cholesterol management developed by the American College of Cardiology, American Heart Association, and 10 other medical societies.
And it is provocative enough to elicit at least four editorials issued the same day across the JAMA family of journals. They highlight key differences between the two documents, among them the USPSTF guidance’s consistent, narrow reliance on 7.5% and 10% cut points for 10-year risk levels as estimated from the ACC/AHA pooled cohort equations (PCE).
The guidance pairs the 10-year risk metric with at least one of only four prescribed CV risk factors to arrive at a limited choice of statin therapy recommendations. But its decision process isn’t bolstered by coronary artery calcium (CAC) scores or the prespecified “risk enhancers” that allowed the ACC/AHA-multisociety guidelines to be applied broadly and still be closely personalized. Those guidelines provide more PCE-based risk tiers for greater discrimination of risk and allow statins to be considered across a broader age group.
The USPSTF guidance’s evidence base consists of 23 clinical trials and three observational studies that directly compared a statin to either placebo or no statin, task force member John B. Wong, MD, Tufts University School of Medicine, Boston, told this news organization.
“In either kind of study, we found that the vast majority of patients had one or more of four risk factors – dyslipidemia, hypertension, diabetes, or smoking. So, when we categorized high risk or increased risk, we included the presence of one or more of those risk factors,” said Dr. Wong, who is director of comparative effectiveness research at Tufts Clinical Translational Science Institute.
‘Sensible and practical’
The USPSTF guidance applies only to adults aged 40-75 without CV signs or symptoms and recommends a statin prescription for persons at “high risk,” that is with an estimated 10-year PCE-based risk for death or CV events of 10% or higher plus at least one of the four risk factors, a level B recommendation.
It recommends that “clinicians selectively offer a statin” to such persons at “increased risk,” who have at least one of the risk factors and an estimated 10-year risk for death or CV events of 7.5% to less than 10%, a level C recommendation. “The likelihood of benefit is smaller in this group” than in persons at high risk, the document states.
“These recommendations from the USPSTF are sensible and practical,” states Salim S. Virani, MD, PhD, DeBakey Veterans Affairs Medical Center, Houston, in a related editorial published the same day in JAMA Network Open. He calls the former B-level recommendation “a conservative approach” and the latter C-level recommendation a “nuanced approach.”
Both are “understandable” given that some studies suggest that the PCE may overestimate the CV risk, Dr. Virani observes. “On the other hand, statin therapy has been shown to be efficacious” at 10-year CV-risk levels down to about 5%.
The USPSTF document “I think is going to perpetuate a problem that we have in this country, which is vast undertreatment of lipids,” Eric D. Peterson, MD, MPH, University of Texas Southwestern Medical Center, Dallas, said in an interview.
“We have a ton of good drugs that can lower cholesterol like crazy. If you lower cholesterol a lot, you improve outcomes,” he said. Dyslipidemia needs to be more widely and consistently treated, but “right now we have a pool of people in primary prevention who undertreat lipids and wait until disease happens – and then cardiologists get engaged. That’s an avoidable miss,” Dr. Peterson adds. He and JAMA Cardiology associate editor Ann Marie Navar, MD, PhD, provided JAMA with an editorial that accompanies the USPSTF guidance.
“My own personal bias would be that the [ACC/AHA-multisociety guidelines] are closer to being right,” Dr. Peterson said. They – unlike the USPSTF guidance – cover people with risk levels below 7.5%, down to at least 5%. They allow risk enhancers like metabolic syndrome, inflammatory diseases, or family history into the decision process. “And they’re more aggressive in diabetes and more aggressive in older people,” he said.
Higher threshold for therapy
The USPSTF guidance also explicitly omits some high-risk groups and makes little accommodation for others who might especially benefit from statins, several of the editorials contend. For example, states a related JAMA Cardiology editorial published the same day, “The USPSTF does not comment on familial hypercholesterolemia or an LDL-C level of 190 mg/dL or higher,” yet they are covered by the ACC/AHA-multispecialty guidelines.
In addition, write the editorialists, led by Neil J. Stone, MD, Northwestern University, Chicago, “the USPSTF uses a slightly higher threshold for initiation of statin therapy” than was used in the ACC/AHA-multisociety guidelines. USPSTF, for example, calls for 10-year risk to reach 10% before recommending a statin prescription.
“One concern about the USPSTF setting the bar higher for statin initiation is that it reduces the number of young patients (age 40-50 years) at risk for premature myocardial infarction considered for treatment,” write Dr. Stone and colleagues.
That may be related to a weakness of the PCE-based decision process. “Because the PCE estimates of 10-year CV disease risk rely so heavily on age, sex, and race, use of these estimates to identify candidates for statins results in significant skewing of the population recommended for statins,” write Dr. Navar and Dr. Peterson in their JAMA editorial.
The risk enhancers in the ACC/AHA-multispecialty guidelines, about a dozen of them, compensate for that limitation to some extent. But the PCE-dominated USPSTF risk estimates will likely miss some groups that could potentially benefit from statin therapy, Dr. Peterson agreed in an interview.
For example, younger adults facing years of high LDL-cholesterol levels could easily have PCE-based 10-year risk below 10%. “Having a high LDL over a lifetime puts you at really high risk,” he said. “Young people are missed even though their longitudinal risk is high.” So, by waiting for the lofty 10% level of risk over 10 years, “we limit the use of medicine that’s pretty cheap and highly effective.”
Dose intensity, adverse events
Also at variance from the ACC/AHA-multispecialty guidelines, the USPSTF states that, “Based on available evidence, use of moderate-intensity statin therapy seems reasonable for the primary prevention of CV disease in most persons.”
The task force specifically explored whether evidence supports some use of high-intensity vs. moderate-intensity statins, Tufts University’s Dr. Wong said. “We found only one study that looked at that particular question, and it didn’t give us a strong answer.” An elevated rosuvastatin-related diabetes risk was apparent in the JUPITER trial, “but for the other studies, we did not find that association.”
Most of the studies that explored statins for reducing risk for a first stroke or myocardial infarction used a moderate-dose statin, Dr. Wong said. “So that’s what we would usually recommend.”
But, Dr. Virani writes, consistent with the ACC/AHA-multispecialty guidelines, “clinicians should consider titrating the intensity of therapy to the risk of the individual.” Persons in certain high-risk primary prevention groups, such as those with end-organ injury from diabetes or LDL cholesterol at least 190 mg/dL, “may derive further benefit from the use of high-intensity statin therapy.”
Low-intensity statins are another potential option, but “in contrast with its 2016 recommendations, the USPSTF no longer recommends use of low-intensity statins in certain situations,” observes a fourth editorial published the same day in JAMA Internal Medicine, with lead author Anand R. Habib, MD, MPhil, and senior author Rita F. Redberg, MD, MSc, both of the University of California, San Francisco. Dr. Redberg is the journal’s editor and has long expressed cautions about statin safety.
“While it is understandable that the Task Force was limited by lack of data on dosing, this change is unfortunate for patients because the frequency of adverse effects increases as the statin dose increases,” the editorial states. Although USPSTF did not find statistically significant harm from the drugs, “in clinical practice, adverse events are commonly reported with use of statins.”
It continues: “At present, there are further reasons to curb our enthusiasm about the use of statins for primary prevention of CV disease.” To illustrate, the editorial questioned primary-prevention statins’ balance of risk vs. clinically meaningful benefit, not benefit that is merely statistically significant.
“The purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention,” the editorial states.
“Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, while the chance of adverse effects is constant across risk categories.”
However, USPSTF states, “In pooled analyses of trial data, statin therapy was not associated with increased risk of study withdrawal due to adverse events or serious adverse events.” Nor did it find significant associations with cancers, liver enzyme abnormalities, or diabetes, including new-onset diabetes.
And, the USPSTF adds, “Evidence on the association between statins and renal or cognitive harms is very limited but does not indicate increased risk.”
USPSTF is supported by the U.S. Agency for Healthcare Research and Quality. Dr. Virani discloses receiving grants from the Department of Veterans Affairs, National Institutes of Health, and the World Heart Federation; and personal fees from the American College of Cardiology. Dr. Peterson discloses serving on the JAMA editorial board and receiving research support to his institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and consulting fees from Novo Nordisk, Bayer, and Novartis. Dr. Navar discloses receiving research support to her institution from Amgen, Bristol-Myers Squibb, Esperion, and Janssen; and receiving honoraria and consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Lilly, Novo Nordisk, Novartis, New Amsterdam, and Pfizer. Dr. Stone discloses receiving an honorarium from Knowledge to Practice, an educational company not associated with the pharmaceutical industry; disclosures for the other authors are in the report. Dr. Redberg discloses receiving research funding from the Arnold Ventures Foundation and the Greenwall Foundation.
A version of this article first appeared on Medscape.com.
FROM JAMA
How much weight does my patient need to lose?
What is the real goal of weight loss? In health care, reducing excess body fat is known to improve many complications faced by patients with obesity. Even modest to moderate weight loss contributes to improvements in health. Normalizing body weight is not required.
While our culture promotes an ideal body size, in the health care setting, our attention must focus on achieving health improvement. We need to be more tolerant of variations in body size if patients are healthy. Of note, varying amounts of weight loss produce improvement in the different complications of obesity, so the amount of weight loss required for improving one condition differs from that required to improve another condition.
When we prescribe weight loss for health improvement, we are trying to reduce both the mechanical burden of fat and the excess ectopic and visceral body fat that is driving disease. The good news about the physiology of weight loss is that we do not need to attain a body mass index (BMI) of 25 or even 30 to have health improvement. The excess abnormal body fat is the first to go!
Losing weight causes a disproportional reduction in ectopic and visceral fat depots. With a 5% weight loss, visceral fat is reduced by 9%. With 16% weight loss, visceral fat is reduced by 30%. Clearing of liver fat is even more dramatic. With 16% weight loss, 65% of liver fat is cleared.
Because ectopic abnormal fat is cleared preferentially with weight loss, it affects different tissues with varying amounts of weight loss.
Weight loss and diabetes
A close relationship exists between weight loss and insulin sensitivity. With just 5% weight loss, insulin sensitivity in the liver and adipose tissue is greatly improved, but while muscle insulin sensitivity is improved at just 5% weight loss, it continues to improve with further weight loss. Indeed, weight loss has enormous benefits in improving glycemia in prediabetes and diabetes.
In patients with impaired glucose tolerance, weight loss of 10% can eliminate progression to type 2 diabetes. In patients with type 2 diabetes who still have beta-cell reserve, 15% weight loss can produce diabetes remission – normoglycemia without diabetes medications.
Weight loss and cardiovascular risk factors
Even very small amounts of weight loss – 3% – can improve triglycerides and glycemia. It takes 5% weight loss to show benefits in systolic and diastolic blood pressure, as well as in HDL and LDL cholesterol levels. For all of these, additional weight loss brings more improvement. Inflammatory markers are more difficult. It takes 10%-15% weight loss to improve most of these – for example, C-reactive protein.
Weight loss and other complications
It takes 10% or more weight loss to demonstrate improvements in symptoms in obstructive sleep apnea and gastroesophageal reflux disease. For knee pain, the relationship to improvement is not based on achieving a percentage loss. Each pound of weight lost can result in a fourfold reduction in the load exerted on the knee per step during daily activities, but it is important to reduce weight before there is structural damage, because weight loss can’t repair damaged knee joints. Moderate weight loss (5%-10%) produces improvements in quality-of-life measures, in urinary stress incontinence symptoms, and in measures of sexual function. It probably takes 15% or more weight loss to demonstrate improvement in cardiovascular events.
Must heavier patients lose more weight?
To answer this question, it is important to think in terms of percent weight loss rather than pounds or kilograms. In large studies of lifestyle intervention, of course individuals with higher BMI lost more weight. But the percentage weight loss was the same across BMI categories: class 1 (BMI 30-35), class 2 (BMI 35-40), class 3 (BMI > 40). Furthermore, the improvement in risk factors was the same across BMI categories. Those with class 3 obesity had the same improvements as those with class 1. This provides further rationale for thinking about weight loss as a percentage from baseline weight rather than as simply a weight-loss goal in pounds.
Goal setting is an important part of any behavioral intervention
At the start of a weight-loss intervention, the health care provider should raise the issue of the goal and the time course for achieving it. Patients often have unrealistic expectations, wanting to achieve large amounts of weight loss rapidly. Unfortunately, popular culture has reinforced this idea with advertisements using “lose 10 pounds the first week” and promoting before-and-after pictures of weight-loss results. The job of the health care provider is to coach and guide the patient in terms of achievable weight loss that can bring health improvement safely. Managing patient expectations is critical to long-term success.
Think in terms of percentage weight loss, not pounds, and set goals at achievable time points
Help patients translate a percent weight-loss goal to a pounds goal at 3, 6, and 12 months. With the emergence of medications approved for chronic weight management with robust weight-loss efficacy, it now is possible to achieve a weight-loss goal of 10% or 15% with regularity, and some patients will be able to achieve 20% or 25% weight loss with newer medications.
We should help our patients set a goal by calculating a goal for certain time points. A good goal for 3 months would be 5% weight loss. For our 200-lb patient, we would translate that to 10 lb in 3 months. For 6 months, the goal should be 10% (20 lb for our 200-lb patient). The usual trajectory of weight loss with lifestyle intervention alone is for a “plateau” at 6 months, although with newer medications, weight loss will continue for more than a year. That 1-year goal might be 15% (30 lb for our 200-lb patient) or even more, based on the patient’s baseline weight and body composition.
Weight-loss calculators can be useful tools for patients and health care providers. They can be found online and include the National Institutes of Health Body Weight Planner and the Pennington Biomedical Weight Loss Predictor Calculator. These tools give patients a realistic expectation of how fast weight loss can occur and provide guidelines to measure success.
Can patients lose too much weight?
In this patient population, losing too much weight is not typically a concern. However, newer medications are achieving average weight losses of 17% and 22% at 62 weeks, as reported by this news organization. There is a wide variation in response to these newer agents which target appetite, and many patients are losing more than the average percentages.
Remembering that the goal of weight loss is the reduction of excess abnormal body fat, we want patients to preserve as much lean mass as possible. Weight-bearing exercise can help during the weight-loss phase, but large or rapid weight loss can be concerning, especially in older individuals. When the BMI drops below 25, we want to watch patients carefully. Measurement of body composition, including bone mineral density, with dual-energy x-ray absorptiometry (DEXA) can help. This is a scenario where dose reduction of antiobesity medication can be indicated, and good clinical judgment is required to keep weight loss at healthy levels.
The future of weight loss
In the past, our strategy has been to promote as much weight loss as possible. With more effective medications, our strategy will have to change to a treat-to-target approach, such as we already use in hypertension and diabetes.
With the ability to produce powerful effects on appetite will come the need to not only target weight loss but to target preservation of lean mass and even to target different approaches for weight-loss maintenance. At present, we have no evidence that stopping medications results in anything other than weight regain. The study of different approaches to weight-loss maintenance will require our full attention.
Dr. Ryan has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, consultant, or trustee for: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand. Received income in an amount equal to or greater than $250 from: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand.
Donna Ryan, MD, is Professor Emerita, Pennington Biomedical Research Center, Louisiana State University, New Orleans.
A version of this article first appeared on Medscape.com.
What is the real goal of weight loss? In health care, reducing excess body fat is known to improve many complications faced by patients with obesity. Even modest to moderate weight loss contributes to improvements in health. Normalizing body weight is not required.
While our culture promotes an ideal body size, in the health care setting, our attention must focus on achieving health improvement. We need to be more tolerant of variations in body size if patients are healthy. Of note, varying amounts of weight loss produce improvement in the different complications of obesity, so the amount of weight loss required for improving one condition differs from that required to improve another condition.
When we prescribe weight loss for health improvement, we are trying to reduce both the mechanical burden of fat and the excess ectopic and visceral body fat that is driving disease. The good news about the physiology of weight loss is that we do not need to attain a body mass index (BMI) of 25 or even 30 to have health improvement. The excess abnormal body fat is the first to go!
Losing weight causes a disproportional reduction in ectopic and visceral fat depots. With a 5% weight loss, visceral fat is reduced by 9%. With 16% weight loss, visceral fat is reduced by 30%. Clearing of liver fat is even more dramatic. With 16% weight loss, 65% of liver fat is cleared.
Because ectopic abnormal fat is cleared preferentially with weight loss, it affects different tissues with varying amounts of weight loss.
Weight loss and diabetes
A close relationship exists between weight loss and insulin sensitivity. With just 5% weight loss, insulin sensitivity in the liver and adipose tissue is greatly improved, but while muscle insulin sensitivity is improved at just 5% weight loss, it continues to improve with further weight loss. Indeed, weight loss has enormous benefits in improving glycemia in prediabetes and diabetes.
In patients with impaired glucose tolerance, weight loss of 10% can eliminate progression to type 2 diabetes. In patients with type 2 diabetes who still have beta-cell reserve, 15% weight loss can produce diabetes remission – normoglycemia without diabetes medications.
Weight loss and cardiovascular risk factors
Even very small amounts of weight loss – 3% – can improve triglycerides and glycemia. It takes 5% weight loss to show benefits in systolic and diastolic blood pressure, as well as in HDL and LDL cholesterol levels. For all of these, additional weight loss brings more improvement. Inflammatory markers are more difficult. It takes 10%-15% weight loss to improve most of these – for example, C-reactive protein.
Weight loss and other complications
It takes 10% or more weight loss to demonstrate improvements in symptoms in obstructive sleep apnea and gastroesophageal reflux disease. For knee pain, the relationship to improvement is not based on achieving a percentage loss. Each pound of weight lost can result in a fourfold reduction in the load exerted on the knee per step during daily activities, but it is important to reduce weight before there is structural damage, because weight loss can’t repair damaged knee joints. Moderate weight loss (5%-10%) produces improvements in quality-of-life measures, in urinary stress incontinence symptoms, and in measures of sexual function. It probably takes 15% or more weight loss to demonstrate improvement in cardiovascular events.
Must heavier patients lose more weight?
To answer this question, it is important to think in terms of percent weight loss rather than pounds or kilograms. In large studies of lifestyle intervention, of course individuals with higher BMI lost more weight. But the percentage weight loss was the same across BMI categories: class 1 (BMI 30-35), class 2 (BMI 35-40), class 3 (BMI > 40). Furthermore, the improvement in risk factors was the same across BMI categories. Those with class 3 obesity had the same improvements as those with class 1. This provides further rationale for thinking about weight loss as a percentage from baseline weight rather than as simply a weight-loss goal in pounds.
Goal setting is an important part of any behavioral intervention
At the start of a weight-loss intervention, the health care provider should raise the issue of the goal and the time course for achieving it. Patients often have unrealistic expectations, wanting to achieve large amounts of weight loss rapidly. Unfortunately, popular culture has reinforced this idea with advertisements using “lose 10 pounds the first week” and promoting before-and-after pictures of weight-loss results. The job of the health care provider is to coach and guide the patient in terms of achievable weight loss that can bring health improvement safely. Managing patient expectations is critical to long-term success.
Think in terms of percentage weight loss, not pounds, and set goals at achievable time points
Help patients translate a percent weight-loss goal to a pounds goal at 3, 6, and 12 months. With the emergence of medications approved for chronic weight management with robust weight-loss efficacy, it now is possible to achieve a weight-loss goal of 10% or 15% with regularity, and some patients will be able to achieve 20% or 25% weight loss with newer medications.
We should help our patients set a goal by calculating a goal for certain time points. A good goal for 3 months would be 5% weight loss. For our 200-lb patient, we would translate that to 10 lb in 3 months. For 6 months, the goal should be 10% (20 lb for our 200-lb patient). The usual trajectory of weight loss with lifestyle intervention alone is for a “plateau” at 6 months, although with newer medications, weight loss will continue for more than a year. That 1-year goal might be 15% (30 lb for our 200-lb patient) or even more, based on the patient’s baseline weight and body composition.
Weight-loss calculators can be useful tools for patients and health care providers. They can be found online and include the National Institutes of Health Body Weight Planner and the Pennington Biomedical Weight Loss Predictor Calculator. These tools give patients a realistic expectation of how fast weight loss can occur and provide guidelines to measure success.
Can patients lose too much weight?
In this patient population, losing too much weight is not typically a concern. However, newer medications are achieving average weight losses of 17% and 22% at 62 weeks, as reported by this news organization. There is a wide variation in response to these newer agents which target appetite, and many patients are losing more than the average percentages.
Remembering that the goal of weight loss is the reduction of excess abnormal body fat, we want patients to preserve as much lean mass as possible. Weight-bearing exercise can help during the weight-loss phase, but large or rapid weight loss can be concerning, especially in older individuals. When the BMI drops below 25, we want to watch patients carefully. Measurement of body composition, including bone mineral density, with dual-energy x-ray absorptiometry (DEXA) can help. This is a scenario where dose reduction of antiobesity medication can be indicated, and good clinical judgment is required to keep weight loss at healthy levels.
The future of weight loss
In the past, our strategy has been to promote as much weight loss as possible. With more effective medications, our strategy will have to change to a treat-to-target approach, such as we already use in hypertension and diabetes.
With the ability to produce powerful effects on appetite will come the need to not only target weight loss but to target preservation of lean mass and even to target different approaches for weight-loss maintenance. At present, we have no evidence that stopping medications results in anything other than weight regain. The study of different approaches to weight-loss maintenance will require our full attention.
Dr. Ryan has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, consultant, or trustee for: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand. Received income in an amount equal to or greater than $250 from: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand.
Donna Ryan, MD, is Professor Emerita, Pennington Biomedical Research Center, Louisiana State University, New Orleans.
A version of this article first appeared on Medscape.com.
What is the real goal of weight loss? In health care, reducing excess body fat is known to improve many complications faced by patients with obesity. Even modest to moderate weight loss contributes to improvements in health. Normalizing body weight is not required.
While our culture promotes an ideal body size, in the health care setting, our attention must focus on achieving health improvement. We need to be more tolerant of variations in body size if patients are healthy. Of note, varying amounts of weight loss produce improvement in the different complications of obesity, so the amount of weight loss required for improving one condition differs from that required to improve another condition.
When we prescribe weight loss for health improvement, we are trying to reduce both the mechanical burden of fat and the excess ectopic and visceral body fat that is driving disease. The good news about the physiology of weight loss is that we do not need to attain a body mass index (BMI) of 25 or even 30 to have health improvement. The excess abnormal body fat is the first to go!
Losing weight causes a disproportional reduction in ectopic and visceral fat depots. With a 5% weight loss, visceral fat is reduced by 9%. With 16% weight loss, visceral fat is reduced by 30%. Clearing of liver fat is even more dramatic. With 16% weight loss, 65% of liver fat is cleared.
Because ectopic abnormal fat is cleared preferentially with weight loss, it affects different tissues with varying amounts of weight loss.
Weight loss and diabetes
A close relationship exists between weight loss and insulin sensitivity. With just 5% weight loss, insulin sensitivity in the liver and adipose tissue is greatly improved, but while muscle insulin sensitivity is improved at just 5% weight loss, it continues to improve with further weight loss. Indeed, weight loss has enormous benefits in improving glycemia in prediabetes and diabetes.
In patients with impaired glucose tolerance, weight loss of 10% can eliminate progression to type 2 diabetes. In patients with type 2 diabetes who still have beta-cell reserve, 15% weight loss can produce diabetes remission – normoglycemia without diabetes medications.
Weight loss and cardiovascular risk factors
Even very small amounts of weight loss – 3% – can improve triglycerides and glycemia. It takes 5% weight loss to show benefits in systolic and diastolic blood pressure, as well as in HDL and LDL cholesterol levels. For all of these, additional weight loss brings more improvement. Inflammatory markers are more difficult. It takes 10%-15% weight loss to improve most of these – for example, C-reactive protein.
Weight loss and other complications
It takes 10% or more weight loss to demonstrate improvements in symptoms in obstructive sleep apnea and gastroesophageal reflux disease. For knee pain, the relationship to improvement is not based on achieving a percentage loss. Each pound of weight lost can result in a fourfold reduction in the load exerted on the knee per step during daily activities, but it is important to reduce weight before there is structural damage, because weight loss can’t repair damaged knee joints. Moderate weight loss (5%-10%) produces improvements in quality-of-life measures, in urinary stress incontinence symptoms, and in measures of sexual function. It probably takes 15% or more weight loss to demonstrate improvement in cardiovascular events.
Must heavier patients lose more weight?
To answer this question, it is important to think in terms of percent weight loss rather than pounds or kilograms. In large studies of lifestyle intervention, of course individuals with higher BMI lost more weight. But the percentage weight loss was the same across BMI categories: class 1 (BMI 30-35), class 2 (BMI 35-40), class 3 (BMI > 40). Furthermore, the improvement in risk factors was the same across BMI categories. Those with class 3 obesity had the same improvements as those with class 1. This provides further rationale for thinking about weight loss as a percentage from baseline weight rather than as simply a weight-loss goal in pounds.
Goal setting is an important part of any behavioral intervention
At the start of a weight-loss intervention, the health care provider should raise the issue of the goal and the time course for achieving it. Patients often have unrealistic expectations, wanting to achieve large amounts of weight loss rapidly. Unfortunately, popular culture has reinforced this idea with advertisements using “lose 10 pounds the first week” and promoting before-and-after pictures of weight-loss results. The job of the health care provider is to coach and guide the patient in terms of achievable weight loss that can bring health improvement safely. Managing patient expectations is critical to long-term success.
Think in terms of percentage weight loss, not pounds, and set goals at achievable time points
Help patients translate a percent weight-loss goal to a pounds goal at 3, 6, and 12 months. With the emergence of medications approved for chronic weight management with robust weight-loss efficacy, it now is possible to achieve a weight-loss goal of 10% or 15% with regularity, and some patients will be able to achieve 20% or 25% weight loss with newer medications.
We should help our patients set a goal by calculating a goal for certain time points. A good goal for 3 months would be 5% weight loss. For our 200-lb patient, we would translate that to 10 lb in 3 months. For 6 months, the goal should be 10% (20 lb for our 200-lb patient). The usual trajectory of weight loss with lifestyle intervention alone is for a “plateau” at 6 months, although with newer medications, weight loss will continue for more than a year. That 1-year goal might be 15% (30 lb for our 200-lb patient) or even more, based on the patient’s baseline weight and body composition.
Weight-loss calculators can be useful tools for patients and health care providers. They can be found online and include the National Institutes of Health Body Weight Planner and the Pennington Biomedical Weight Loss Predictor Calculator. These tools give patients a realistic expectation of how fast weight loss can occur and provide guidelines to measure success.
Can patients lose too much weight?
In this patient population, losing too much weight is not typically a concern. However, newer medications are achieving average weight losses of 17% and 22% at 62 weeks, as reported by this news organization. There is a wide variation in response to these newer agents which target appetite, and many patients are losing more than the average percentages.
Remembering that the goal of weight loss is the reduction of excess abnormal body fat, we want patients to preserve as much lean mass as possible. Weight-bearing exercise can help during the weight-loss phase, but large or rapid weight loss can be concerning, especially in older individuals. When the BMI drops below 25, we want to watch patients carefully. Measurement of body composition, including bone mineral density, with dual-energy x-ray absorptiometry (DEXA) can help. This is a scenario where dose reduction of antiobesity medication can be indicated, and good clinical judgment is required to keep weight loss at healthy levels.
The future of weight loss
In the past, our strategy has been to promote as much weight loss as possible. With more effective medications, our strategy will have to change to a treat-to-target approach, such as we already use in hypertension and diabetes.
With the ability to produce powerful effects on appetite will come the need to not only target weight loss but to target preservation of lean mass and even to target different approaches for weight-loss maintenance. At present, we have no evidence that stopping medications results in anything other than weight regain. The study of different approaches to weight-loss maintenance will require our full attention.
Dr. Ryan has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, consultant, or trustee for: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand. Received income in an amount equal to or greater than $250 from: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand.
Donna Ryan, MD, is Professor Emerita, Pennington Biomedical Research Center, Louisiana State University, New Orleans.
A version of this article first appeared on Medscape.com.
Are artificial sweeteners really harmless?
New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.
Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.
The study was published online in the journal Cell.
Gut reaction?
Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.
They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.
Each sweetener “significantly and distinctly” altered stool and oral microbiome, and two of them (saccharin and sucralose) significantly impaired glucose tolerance, the researchers reported.
“Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non–NNS-consuming recipient mice,” they said.
They noted that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual’s microbiome.
“We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies,” Dr. Elinav said in a news release.
For now, Dr. Elinav said it’s his personal view that “drinking only water seems to be the best solution.”
Weighing the evidence
Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.
Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).
“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.
Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”
The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.
“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.
Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.
“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.
Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.
“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.
The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”
They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”
Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”
The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 8/29/22.
New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.
Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.
The study was published online in the journal Cell.
Gut reaction?
Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.
They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.
Each sweetener “significantly and distinctly” altered stool and oral microbiome, and two of them (saccharin and sucralose) significantly impaired glucose tolerance, the researchers reported.
“Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non–NNS-consuming recipient mice,” they said.
They noted that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual’s microbiome.
“We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies,” Dr. Elinav said in a news release.
For now, Dr. Elinav said it’s his personal view that “drinking only water seems to be the best solution.”
Weighing the evidence
Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.
Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).
“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.
Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”
The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.
“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.
Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.
“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.
Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.
“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.
The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”
They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”
Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”
The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 8/29/22.
New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.
Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.
The study was published online in the journal Cell.
Gut reaction?
Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.
They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.
Each sweetener “significantly and distinctly” altered stool and oral microbiome, and two of them (saccharin and sucralose) significantly impaired glucose tolerance, the researchers reported.
“Importantly, by performing extensive fecal transplantation of human microbiomes into germ-free mice, we demonstrate a causal and individualized link between NNS-altered microbiomes and glucose intolerance developing in non–NNS-consuming recipient mice,” they said.
They noted that the effects of these sweeteners will likely vary from person to person because of the unique composition of an individual’s microbiome.
“We need to raise awareness of the fact that NNS are not inert to the human body as we originally believed. With that said, the clinical health implications of the changes they may elicit in humans remain unknown and merit future long-term studies,” Dr. Elinav said in a news release.
For now, Dr. Elinav said it’s his personal view that “drinking only water seems to be the best solution.”
Weighing the evidence
Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.
Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).
“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.
Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”
The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.
“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.
Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.
“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.
Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.
“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.
The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”
They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”
Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”
The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 8/29/22.
Guidelines on GLP1RAs and continuous glucose monitors are among biggest news in diabetes
glucagonlike peptide-1 receptor agonists (GLP1RAs) and continuous glucose monitoring (CGM) technology. I am hoping my discussion about these major advances in this edition of Highlights will be helpful to those caring for patients with diabetes.
Tirzepatide
The first GLP1RA, exenatide, was released in April 2005. Since then, numerous daily and weekly drugs of this class have been developed. We’ve learned they are effective glucose lowering drugs, and the weekly agents dulaglutide and semaglutide have shown impressive weight reduction properties as well as cardiovascular benefits.
Secondary outcomes have also shown renal benefits to these agents, and studies for primary renal efficacy are pending. Due to all of these properties, the GLP1RAs are recommended as the first injectable for the treatment of type 2 diabetes, prior to insulin initiation.1
The next generation of these agents are a combination of a GLP1RA and a glucose-dependent insulinotropic polypeptide (GIP). Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying, and has central effects inducing satiety.
We now understand that GIP is the main incretin hormone in those without diabetes, causative of most of the incretin effects. But the insulin response after GIP secretion in type 2 diabetes is strongly reduced. It is now appreciated that this poor effect of GIP can be reduced when used in combination with a GLP1RA. This combination incretin, called by some a “twincretin,” is the basis for the drug tirzepatide which was approved by the Food and Drug Administration in May of 2022.
The data supporting this agent for both diabetes and obesity are impressive. For example, in a 40-week study with a baseline HbA1c of 8.0%, those randomized to tirzepatide at 5 mg, 10 mg, and 15 mg had HbA1c reductions of 1.87%, 1.89%, and 2.07% respectively.2 Over 81% at all doses had HbA1c levels less than 6.5% at 40 weeks.
For the 5-mg, 10-mg, and 15-mg doses, weight change from baseline was 7.9%, 9.3%, and 11.0% respectively. Like older GLP1RAs, gastrointestinal side effects were the main problem. For the three doses, 3%, 5%, and 7%, respectively, had to stop the drug, compared with the 3% who stopped taking the placebo. In another study, tirzepatide was noninferior or superior at all three doses compared with semaglutide 1 mg weekly.3
In a population without diabetes, with 40% of patients having prediabetes, weight loss percentages for the three doses were 15.0%, 19.5%, and 20.9% respectively.4 Discontinuation percentages due to side effects were 4%-7%. The exciting part is we now have a drug that approaches weight loss from bariatric surgery. The cardiovascular and renal outcome trials are now underway, but the enthusiasm for this drug is clear from the data.
Like other GLP1RAs, the key is to start low and go slowly. It is recommended to start tirzepatide at 2.5 mg four times a week, then increase to 5 mg. Due to gastrointestinal side effects, some patients will do better at the lower dose before increasing. For those switching from another GLP1RA, there are no data to guide us but, in my practice, I start those patients at 5 mg weekly.
Continuous glucose monitoring
Data continue to accumulate that this form of glycemic self-monitoring is effective to reduce HbA1c levels and minimize hypoglycemia in both type 1 and type 2 diabetes. The most important change to the 2022 American Diabetes Association (ADA) standards of care is recognizing CGM as level A evidence for those receiving basal insulin without mealtime insulin.5 There are four CGMs on the market, but most of the market uses the Dexcom G6 or the Libre 2. Both of these devices will be updated within the next few months to newer generation sensors.
While there are similarities and differences between the two devices, by late 2022 and early 2023 changes to both will reduce the dissimilarities.
The next generation Libre (Libre 3) will be continuous, and “scanning” will no longer be required. For those unable to get insurance to cover CGM, the Libre will continue to be more affordable than the Dexcom. Alerts will be present on both, but the Dexcom G7 will be approved for both the arm and the abdomen. The Dexcom also can communicate with several automated insulin delivery systems and data can be shared real-time with family members.
For clinicians just starting patients on this technology, my suggestion is to focus on one system so both the provider and staff can become familiar with it. It is key to review downloaded glucose metrics, in addition to the “ambulatory glucose profile,” a graphic overview of daily glycemia where patterns can be identified. It is also helpful to ask for assistance from endocrinologists who have experience with CGMs, in addition to the representatives of the companies.
COVID-19 and new-onset diabetes
From the beginning of the COVID 19 pandemic in 2020, it was clear that stress hyperglycemia and glucose dysregulation was an important observation for those infected. What was not known at the time is that for some, the hyperglycemia continued, and permanent diabetes ensued.
In one study of over 2.7 million U.S. veterans, men infected with COVID-19, but not women, were at a higher risk of new incident diabetes at 120 days after infection compared to no infection (odds ratio for men = 2.56).6
Another literature review using meta-analyses and cross-sectional studies concluded new-onset diabetes following COVID-19 infection can have a varied phenotype, with no risk factors, presenting from diabetic ketoacidosis to milder forms of diabetes.7
The current thought is that COVID-19 binds to the ACE2 and TMPRSS2 receptors which appear to be located on the beta-cells in the islet, resulting in insulin deficiency, in addition to the insulin resistance that seems to persist after the acute infection. Much more needs to be learned about this, but clinicians need to appreciate this appears to be a new form of diabetes and optimal treatments are not yet clear.
Dr. Hirsch is an endocrinologist, professor of medicine, and diabetes treatment and teaching chair at the University of Washington, Seattle. He has received research grant support from Dexcom and Insulet and has provided consulting to Abbott, Roche, Lifescan, and GWave. You can contact him at imnews@mdedge.com.
References
1. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143.
2. Rosenstock J et al. Efficacy and safety of a novel GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet. 2021;398:143-55.
3. Frias JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15.
4. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205-16.
5. American Diabetes Association Professional Practice Committee. Diabetes technology: Standards of Medical Care in Diabetes–2022. Diabetes Care. 2022;45(Suppl 1):S97-S112.
6. Wander PL et al. The incidence of diabetes in 2,777,768 veterans with and without recent SARS-CoV-2 infection. Diabetes Care 2022;45:782-8.
7. Joshi SC and Pozzilli P. COVID-19 induced diabetes: A novel presentation. Diabetes Res Clin Pract. 2022 Aug 6;191:110034.
glucagonlike peptide-1 receptor agonists (GLP1RAs) and continuous glucose monitoring (CGM) technology. I am hoping my discussion about these major advances in this edition of Highlights will be helpful to those caring for patients with diabetes.
Tirzepatide
The first GLP1RA, exenatide, was released in April 2005. Since then, numerous daily and weekly drugs of this class have been developed. We’ve learned they are effective glucose lowering drugs, and the weekly agents dulaglutide and semaglutide have shown impressive weight reduction properties as well as cardiovascular benefits.
Secondary outcomes have also shown renal benefits to these agents, and studies for primary renal efficacy are pending. Due to all of these properties, the GLP1RAs are recommended as the first injectable for the treatment of type 2 diabetes, prior to insulin initiation.1
The next generation of these agents are a combination of a GLP1RA and a glucose-dependent insulinotropic polypeptide (GIP). Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying, and has central effects inducing satiety.
We now understand that GIP is the main incretin hormone in those without diabetes, causative of most of the incretin effects. But the insulin response after GIP secretion in type 2 diabetes is strongly reduced. It is now appreciated that this poor effect of GIP can be reduced when used in combination with a GLP1RA. This combination incretin, called by some a “twincretin,” is the basis for the drug tirzepatide which was approved by the Food and Drug Administration in May of 2022.
The data supporting this agent for both diabetes and obesity are impressive. For example, in a 40-week study with a baseline HbA1c of 8.0%, those randomized to tirzepatide at 5 mg, 10 mg, and 15 mg had HbA1c reductions of 1.87%, 1.89%, and 2.07% respectively.2 Over 81% at all doses had HbA1c levels less than 6.5% at 40 weeks.
For the 5-mg, 10-mg, and 15-mg doses, weight change from baseline was 7.9%, 9.3%, and 11.0% respectively. Like older GLP1RAs, gastrointestinal side effects were the main problem. For the three doses, 3%, 5%, and 7%, respectively, had to stop the drug, compared with the 3% who stopped taking the placebo. In another study, tirzepatide was noninferior or superior at all three doses compared with semaglutide 1 mg weekly.3
In a population without diabetes, with 40% of patients having prediabetes, weight loss percentages for the three doses were 15.0%, 19.5%, and 20.9% respectively.4 Discontinuation percentages due to side effects were 4%-7%. The exciting part is we now have a drug that approaches weight loss from bariatric surgery. The cardiovascular and renal outcome trials are now underway, but the enthusiasm for this drug is clear from the data.
Like other GLP1RAs, the key is to start low and go slowly. It is recommended to start tirzepatide at 2.5 mg four times a week, then increase to 5 mg. Due to gastrointestinal side effects, some patients will do better at the lower dose before increasing. For those switching from another GLP1RA, there are no data to guide us but, in my practice, I start those patients at 5 mg weekly.
Continuous glucose monitoring
Data continue to accumulate that this form of glycemic self-monitoring is effective to reduce HbA1c levels and minimize hypoglycemia in both type 1 and type 2 diabetes. The most important change to the 2022 American Diabetes Association (ADA) standards of care is recognizing CGM as level A evidence for those receiving basal insulin without mealtime insulin.5 There are four CGMs on the market, but most of the market uses the Dexcom G6 or the Libre 2. Both of these devices will be updated within the next few months to newer generation sensors.
While there are similarities and differences between the two devices, by late 2022 and early 2023 changes to both will reduce the dissimilarities.
The next generation Libre (Libre 3) will be continuous, and “scanning” will no longer be required. For those unable to get insurance to cover CGM, the Libre will continue to be more affordable than the Dexcom. Alerts will be present on both, but the Dexcom G7 will be approved for both the arm and the abdomen. The Dexcom also can communicate with several automated insulin delivery systems and data can be shared real-time with family members.
For clinicians just starting patients on this technology, my suggestion is to focus on one system so both the provider and staff can become familiar with it. It is key to review downloaded glucose metrics, in addition to the “ambulatory glucose profile,” a graphic overview of daily glycemia where patterns can be identified. It is also helpful to ask for assistance from endocrinologists who have experience with CGMs, in addition to the representatives of the companies.
COVID-19 and new-onset diabetes
From the beginning of the COVID 19 pandemic in 2020, it was clear that stress hyperglycemia and glucose dysregulation was an important observation for those infected. What was not known at the time is that for some, the hyperglycemia continued, and permanent diabetes ensued.
In one study of over 2.7 million U.S. veterans, men infected with COVID-19, but not women, were at a higher risk of new incident diabetes at 120 days after infection compared to no infection (odds ratio for men = 2.56).6
Another literature review using meta-analyses and cross-sectional studies concluded new-onset diabetes following COVID-19 infection can have a varied phenotype, with no risk factors, presenting from diabetic ketoacidosis to milder forms of diabetes.7
The current thought is that COVID-19 binds to the ACE2 and TMPRSS2 receptors which appear to be located on the beta-cells in the islet, resulting in insulin deficiency, in addition to the insulin resistance that seems to persist after the acute infection. Much more needs to be learned about this, but clinicians need to appreciate this appears to be a new form of diabetes and optimal treatments are not yet clear.
Dr. Hirsch is an endocrinologist, professor of medicine, and diabetes treatment and teaching chair at the University of Washington, Seattle. He has received research grant support from Dexcom and Insulet and has provided consulting to Abbott, Roche, Lifescan, and GWave. You can contact him at imnews@mdedge.com.
References
1. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143.
2. Rosenstock J et al. Efficacy and safety of a novel GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet. 2021;398:143-55.
3. Frias JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15.
4. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205-16.
5. American Diabetes Association Professional Practice Committee. Diabetes technology: Standards of Medical Care in Diabetes–2022. Diabetes Care. 2022;45(Suppl 1):S97-S112.
6. Wander PL et al. The incidence of diabetes in 2,777,768 veterans with and without recent SARS-CoV-2 infection. Diabetes Care 2022;45:782-8.
7. Joshi SC and Pozzilli P. COVID-19 induced diabetes: A novel presentation. Diabetes Res Clin Pract. 2022 Aug 6;191:110034.
glucagonlike peptide-1 receptor agonists (GLP1RAs) and continuous glucose monitoring (CGM) technology. I am hoping my discussion about these major advances in this edition of Highlights will be helpful to those caring for patients with diabetes.
Tirzepatide
The first GLP1RA, exenatide, was released in April 2005. Since then, numerous daily and weekly drugs of this class have been developed. We’ve learned they are effective glucose lowering drugs, and the weekly agents dulaglutide and semaglutide have shown impressive weight reduction properties as well as cardiovascular benefits.
Secondary outcomes have also shown renal benefits to these agents, and studies for primary renal efficacy are pending. Due to all of these properties, the GLP1RAs are recommended as the first injectable for the treatment of type 2 diabetes, prior to insulin initiation.1
The next generation of these agents are a combination of a GLP1RA and a glucose-dependent insulinotropic polypeptide (GIP). Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying, and has central effects inducing satiety.
We now understand that GIP is the main incretin hormone in those without diabetes, causative of most of the incretin effects. But the insulin response after GIP secretion in type 2 diabetes is strongly reduced. It is now appreciated that this poor effect of GIP can be reduced when used in combination with a GLP1RA. This combination incretin, called by some a “twincretin,” is the basis for the drug tirzepatide which was approved by the Food and Drug Administration in May of 2022.
The data supporting this agent for both diabetes and obesity are impressive. For example, in a 40-week study with a baseline HbA1c of 8.0%, those randomized to tirzepatide at 5 mg, 10 mg, and 15 mg had HbA1c reductions of 1.87%, 1.89%, and 2.07% respectively.2 Over 81% at all doses had HbA1c levels less than 6.5% at 40 weeks.
For the 5-mg, 10-mg, and 15-mg doses, weight change from baseline was 7.9%, 9.3%, and 11.0% respectively. Like older GLP1RAs, gastrointestinal side effects were the main problem. For the three doses, 3%, 5%, and 7%, respectively, had to stop the drug, compared with the 3% who stopped taking the placebo. In another study, tirzepatide was noninferior or superior at all three doses compared with semaglutide 1 mg weekly.3
In a population without diabetes, with 40% of patients having prediabetes, weight loss percentages for the three doses were 15.0%, 19.5%, and 20.9% respectively.4 Discontinuation percentages due to side effects were 4%-7%. The exciting part is we now have a drug that approaches weight loss from bariatric surgery. The cardiovascular and renal outcome trials are now underway, but the enthusiasm for this drug is clear from the data.
Like other GLP1RAs, the key is to start low and go slowly. It is recommended to start tirzepatide at 2.5 mg four times a week, then increase to 5 mg. Due to gastrointestinal side effects, some patients will do better at the lower dose before increasing. For those switching from another GLP1RA, there are no data to guide us but, in my practice, I start those patients at 5 mg weekly.
Continuous glucose monitoring
Data continue to accumulate that this form of glycemic self-monitoring is effective to reduce HbA1c levels and minimize hypoglycemia in both type 1 and type 2 diabetes. The most important change to the 2022 American Diabetes Association (ADA) standards of care is recognizing CGM as level A evidence for those receiving basal insulin without mealtime insulin.5 There are four CGMs on the market, but most of the market uses the Dexcom G6 or the Libre 2. Both of these devices will be updated within the next few months to newer generation sensors.
While there are similarities and differences between the two devices, by late 2022 and early 2023 changes to both will reduce the dissimilarities.
The next generation Libre (Libre 3) will be continuous, and “scanning” will no longer be required. For those unable to get insurance to cover CGM, the Libre will continue to be more affordable than the Dexcom. Alerts will be present on both, but the Dexcom G7 will be approved for both the arm and the abdomen. The Dexcom also can communicate with several automated insulin delivery systems and data can be shared real-time with family members.
For clinicians just starting patients on this technology, my suggestion is to focus on one system so both the provider and staff can become familiar with it. It is key to review downloaded glucose metrics, in addition to the “ambulatory glucose profile,” a graphic overview of daily glycemia where patterns can be identified. It is also helpful to ask for assistance from endocrinologists who have experience with CGMs, in addition to the representatives of the companies.
COVID-19 and new-onset diabetes
From the beginning of the COVID 19 pandemic in 2020, it was clear that stress hyperglycemia and glucose dysregulation was an important observation for those infected. What was not known at the time is that for some, the hyperglycemia continued, and permanent diabetes ensued.
In one study of over 2.7 million U.S. veterans, men infected with COVID-19, but not women, were at a higher risk of new incident diabetes at 120 days after infection compared to no infection (odds ratio for men = 2.56).6
Another literature review using meta-analyses and cross-sectional studies concluded new-onset diabetes following COVID-19 infection can have a varied phenotype, with no risk factors, presenting from diabetic ketoacidosis to milder forms of diabetes.7
The current thought is that COVID-19 binds to the ACE2 and TMPRSS2 receptors which appear to be located on the beta-cells in the islet, resulting in insulin deficiency, in addition to the insulin resistance that seems to persist after the acute infection. Much more needs to be learned about this, but clinicians need to appreciate this appears to be a new form of diabetes and optimal treatments are not yet clear.
Dr. Hirsch is an endocrinologist, professor of medicine, and diabetes treatment and teaching chair at the University of Washington, Seattle. He has received research grant support from Dexcom and Insulet and has provided consulting to Abbott, Roche, Lifescan, and GWave. You can contact him at imnews@mdedge.com.
References
1. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143.
2. Rosenstock J et al. Efficacy and safety of a novel GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet. 2021;398:143-55.
3. Frias JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15.
4. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205-16.
5. American Diabetes Association Professional Practice Committee. Diabetes technology: Standards of Medical Care in Diabetes–2022. Diabetes Care. 2022;45(Suppl 1):S97-S112.
6. Wander PL et al. The incidence of diabetes in 2,777,768 veterans with and without recent SARS-CoV-2 infection. Diabetes Care 2022;45:782-8.
7. Joshi SC and Pozzilli P. COVID-19 induced diabetes: A novel presentation. Diabetes Res Clin Pract. 2022 Aug 6;191:110034.
‘Obesity paradox’ in AFib challenged as mortality climbs with BMI
The relationship between body mass index (BMI) and all-cause mortality in patients with atrial fibrillation (AFib) is U-shaped, with the risk highest in those who are underweight or severely obese and lowest in patients defined simply as obese, a registry analysis suggests. It also showed a similar relationship between BMI and risk for new or worsening heart failure (HF).
Mortality bottomed out at a BMI of about 30-35 kg/m2, which suggests that mild obesity was protective, compared even with “normal-weight” or “overweight” BMI. Still, mortality went up sharply from there with rising BMI.
But higher BMI, a surrogate for obesity, apparently didn’t worsen outcomes by itself. The risk for death from any cause at higher obesity levels was found to depend a lot on related risk factors and comorbidities when the analysis controlled for conditions such as diabetes and hypertension.
The findings suggest an inverse relationship between BMI and all-cause mortality in AFib only for patients with BMI less than about 30. They therefore argue against any “obesity paradox” in AFib that posits consistently better survival with increasing levels of obesity, say researchers, based on their analysis of patients with new-onset AFib in the GARFIELD-AF registry.
“It’s common practice now for clinicians to discuss weight within a clinic setting when they’re talking to their AFib patients,” observed Christian Fielder Camm, BM, BCh, University of Oxford (England), and Royal Berkshire NHS Foundation Trust, Reading, England. So studies suggesting an inverse association between BMI and AFib-related risk can be a concern.
Such studies “seem to suggest that once you’ve got AFib, maintaining a high or very high BMI may in some way be protective – which is contrary to what would seem to make sense and certainly contrary to what our results have shown,” Dr. Camm told this news organization.
“I think that having further evidence now to suggest, actually, that greater BMI is associated with a greater risk of all-cause mortality and heart failure helps reframe that discussion at the physician-patient interaction level more clearly, and ensures that we’re able to talk to our patients appropriately about risks associated with BMI and atrial fibrillation,” said Dr. Camm, who is lead author on the analysis published in Open Heart.
“Obesity is a cause of most cardiovascular diseases, but [these] data would support that being overweight or having mild obesity does not increase the risk,” observed Carl J. Lavie, MD, of the John Ochsner Heart and Vascular Institute, New Orleans, La., and the Ochsner Clinical School at the University of Queensland, Brisbane, Australia.
“At a BMI of 40, it’s very important for them to lose weight for their long-term prognosis,” Dr. Lavie noted, but “at a BMI of 30, the important thing would be to prevent further weight gain. And if they could keep their BMI of 30, they should have a good prognosis. Their prognosis would be particularly good if they didn’t gain weight and put themselves in a more extreme obesity class that is associated with worse risk.”
The current analysis, Dr. Lavie said, “is way better than the AFFIRM study,” which yielded an obesity-paradox report on its patients with AFib about a dozen years ago. “It’s got more data, more numbers, more statistical power,” and breaks BMI into more categories.
That previous analysis based on the influential AFFIRM randomized trial separated its 4,060 patients with AFib into normal (BMI, 18.5-25), overweight (BMI, 25-30), and obese (BMI, > 30) categories, per the convention at the time. It concluded that “obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.”
Bleeding risk on oral anticoagulants
Also noteworthy in the current analysis, variation in BMI didn’t seem to affect mortality or risk for major bleeding or nonhemorrhagic stroke according to choice of oral anticoagulant – whether a new oral anticoagulant (NOAC) or a vitamin K antagonist (VKA).
“We saw that even in the obese and extremely obese group, all-cause mortality was lower in the group taking NOACs, compared with taking warfarin,” Dr. Camm observed, “which goes against the idea that we would need any kind of dose adjustments for increased BMI.”
Indeed, the report notes, use of NOACs, compared with VKA, was associated with a 23% drop in risk for death among patients who were either normal weight or overweight and also in those who were obese or extremely obese.
Those findings “are basically saying that the NOACs look better than warfarin regardless of weight,” agreed Dr. Lavie. “The problem is that the study is not very powered.”
Whereas the benefits of NOACs, compared to VKA, seem similar for patients with a BMI of 30 or 34, compared with a BMI of 23, for example, “none of the studies has many people with 50 BMI.” Many clinicians “feel uncomfortable giving the same dose of NOAC to somebody who has a 60 BMI,” he said. At least with warfarin, “you can check the INR [international normalized ratio].”
The current analysis included 40,482 patients with recently diagnosed AFib and at least one other stroke risk factor from among the registry’s more than 50,000 patients from 35 countries, enrolled from 2010 to 2016. They were followed for 2 years.
The 703 patients with BMI under 18.5 at AFib diagnosis were classified per World Health Organization definitions as underweight; the 13,095 with BMI 18.5-25 as normal weight; the 15,043 with BMI 25-30 as overweight; the 7,560 with BMI 30-35 as obese; and the 4,081 with BMI above 35 as extremely obese. Their ages averaged 71 years, and 55.6% were men.
BMI effects on different outcomes
Relationships between BMI and all-cause mortality and between BMI and new or worsening HF emerged as U-shaped, the risk climbing with both increasing and decreasing BMI. The nadir BMI for risk was about 30 in the case of mortality and about 25 for new or worsening HF.
The all-cause mortality risk rose by 32% for every 5 BMI points lower than a BMI of 30, and by 16% for every 5 BMI points higher than 30, in a partially adjusted analysis. The risk for new or worsening HF rose significantly with increasing but not decreasing BMI, and the reverse was observed for the endpoint of major bleeding.
The effect of BMI on all-cause mortality was “substantially attenuated” when the analysis was further adjusted with “likely mediators of any association between BMI and outcomes,” including hypertension, diabetes, HF, cerebrovascular events, and history of bleeding, Dr. Camm said.
That blunted BMI-mortality relationship, he said, “suggests that a lot of the effect is mediated through relatively traditional risk factors like hypertension and diabetes.”
The 2010 AFFIRM analysis by BMI, Dr. Lavie noted, “didn’t even look at the underweight; they actually threw them out.” Yet, such patients with AFib, who tend to be extremely frail or have chronic diseases or conditions other than the arrhythmia, are common. A take-home of the current study is that “the underweight with atrial fibrillation have a really bad prognosis.”
That message isn’t heard as much, he observed, “but is as important as saying that BMI 30 has the best prognosis. The worst prognosis is with the underweight or the really extreme obese.”
Dr. Camm discloses research funding from the British Heart Foundation. Disclosures for the other authors are in the report. Dr. Lavie has previously disclosed serving as a speaker and consultant for PAI Health and DSM Nutritional Products and is the author of “The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier” (Avery, 2014).
A version of this article first appeared on Medscape.com.
The relationship between body mass index (BMI) and all-cause mortality in patients with atrial fibrillation (AFib) is U-shaped, with the risk highest in those who are underweight or severely obese and lowest in patients defined simply as obese, a registry analysis suggests. It also showed a similar relationship between BMI and risk for new or worsening heart failure (HF).
Mortality bottomed out at a BMI of about 30-35 kg/m2, which suggests that mild obesity was protective, compared even with “normal-weight” or “overweight” BMI. Still, mortality went up sharply from there with rising BMI.
But higher BMI, a surrogate for obesity, apparently didn’t worsen outcomes by itself. The risk for death from any cause at higher obesity levels was found to depend a lot on related risk factors and comorbidities when the analysis controlled for conditions such as diabetes and hypertension.
The findings suggest an inverse relationship between BMI and all-cause mortality in AFib only for patients with BMI less than about 30. They therefore argue against any “obesity paradox” in AFib that posits consistently better survival with increasing levels of obesity, say researchers, based on their analysis of patients with new-onset AFib in the GARFIELD-AF registry.
“It’s common practice now for clinicians to discuss weight within a clinic setting when they’re talking to their AFib patients,” observed Christian Fielder Camm, BM, BCh, University of Oxford (England), and Royal Berkshire NHS Foundation Trust, Reading, England. So studies suggesting an inverse association between BMI and AFib-related risk can be a concern.
Such studies “seem to suggest that once you’ve got AFib, maintaining a high or very high BMI may in some way be protective – which is contrary to what would seem to make sense and certainly contrary to what our results have shown,” Dr. Camm told this news organization.
“I think that having further evidence now to suggest, actually, that greater BMI is associated with a greater risk of all-cause mortality and heart failure helps reframe that discussion at the physician-patient interaction level more clearly, and ensures that we’re able to talk to our patients appropriately about risks associated with BMI and atrial fibrillation,” said Dr. Camm, who is lead author on the analysis published in Open Heart.
“Obesity is a cause of most cardiovascular diseases, but [these] data would support that being overweight or having mild obesity does not increase the risk,” observed Carl J. Lavie, MD, of the John Ochsner Heart and Vascular Institute, New Orleans, La., and the Ochsner Clinical School at the University of Queensland, Brisbane, Australia.
“At a BMI of 40, it’s very important for them to lose weight for their long-term prognosis,” Dr. Lavie noted, but “at a BMI of 30, the important thing would be to prevent further weight gain. And if they could keep their BMI of 30, they should have a good prognosis. Their prognosis would be particularly good if they didn’t gain weight and put themselves in a more extreme obesity class that is associated with worse risk.”
The current analysis, Dr. Lavie said, “is way better than the AFFIRM study,” which yielded an obesity-paradox report on its patients with AFib about a dozen years ago. “It’s got more data, more numbers, more statistical power,” and breaks BMI into more categories.
That previous analysis based on the influential AFFIRM randomized trial separated its 4,060 patients with AFib into normal (BMI, 18.5-25), overweight (BMI, 25-30), and obese (BMI, > 30) categories, per the convention at the time. It concluded that “obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.”
Bleeding risk on oral anticoagulants
Also noteworthy in the current analysis, variation in BMI didn’t seem to affect mortality or risk for major bleeding or nonhemorrhagic stroke according to choice of oral anticoagulant – whether a new oral anticoagulant (NOAC) or a vitamin K antagonist (VKA).
“We saw that even in the obese and extremely obese group, all-cause mortality was lower in the group taking NOACs, compared with taking warfarin,” Dr. Camm observed, “which goes against the idea that we would need any kind of dose adjustments for increased BMI.”
Indeed, the report notes, use of NOACs, compared with VKA, was associated with a 23% drop in risk for death among patients who were either normal weight or overweight and also in those who were obese or extremely obese.
Those findings “are basically saying that the NOACs look better than warfarin regardless of weight,” agreed Dr. Lavie. “The problem is that the study is not very powered.”
Whereas the benefits of NOACs, compared to VKA, seem similar for patients with a BMI of 30 or 34, compared with a BMI of 23, for example, “none of the studies has many people with 50 BMI.” Many clinicians “feel uncomfortable giving the same dose of NOAC to somebody who has a 60 BMI,” he said. At least with warfarin, “you can check the INR [international normalized ratio].”
The current analysis included 40,482 patients with recently diagnosed AFib and at least one other stroke risk factor from among the registry’s more than 50,000 patients from 35 countries, enrolled from 2010 to 2016. They were followed for 2 years.
The 703 patients with BMI under 18.5 at AFib diagnosis were classified per World Health Organization definitions as underweight; the 13,095 with BMI 18.5-25 as normal weight; the 15,043 with BMI 25-30 as overweight; the 7,560 with BMI 30-35 as obese; and the 4,081 with BMI above 35 as extremely obese. Their ages averaged 71 years, and 55.6% were men.
BMI effects on different outcomes
Relationships between BMI and all-cause mortality and between BMI and new or worsening HF emerged as U-shaped, the risk climbing with both increasing and decreasing BMI. The nadir BMI for risk was about 30 in the case of mortality and about 25 for new or worsening HF.
The all-cause mortality risk rose by 32% for every 5 BMI points lower than a BMI of 30, and by 16% for every 5 BMI points higher than 30, in a partially adjusted analysis. The risk for new or worsening HF rose significantly with increasing but not decreasing BMI, and the reverse was observed for the endpoint of major bleeding.
The effect of BMI on all-cause mortality was “substantially attenuated” when the analysis was further adjusted with “likely mediators of any association between BMI and outcomes,” including hypertension, diabetes, HF, cerebrovascular events, and history of bleeding, Dr. Camm said.
That blunted BMI-mortality relationship, he said, “suggests that a lot of the effect is mediated through relatively traditional risk factors like hypertension and diabetes.”
The 2010 AFFIRM analysis by BMI, Dr. Lavie noted, “didn’t even look at the underweight; they actually threw them out.” Yet, such patients with AFib, who tend to be extremely frail or have chronic diseases or conditions other than the arrhythmia, are common. A take-home of the current study is that “the underweight with atrial fibrillation have a really bad prognosis.”
That message isn’t heard as much, he observed, “but is as important as saying that BMI 30 has the best prognosis. The worst prognosis is with the underweight or the really extreme obese.”
Dr. Camm discloses research funding from the British Heart Foundation. Disclosures for the other authors are in the report. Dr. Lavie has previously disclosed serving as a speaker and consultant for PAI Health and DSM Nutritional Products and is the author of “The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier” (Avery, 2014).
A version of this article first appeared on Medscape.com.
The relationship between body mass index (BMI) and all-cause mortality in patients with atrial fibrillation (AFib) is U-shaped, with the risk highest in those who are underweight or severely obese and lowest in patients defined simply as obese, a registry analysis suggests. It also showed a similar relationship between BMI and risk for new or worsening heart failure (HF).
Mortality bottomed out at a BMI of about 30-35 kg/m2, which suggests that mild obesity was protective, compared even with “normal-weight” or “overweight” BMI. Still, mortality went up sharply from there with rising BMI.
But higher BMI, a surrogate for obesity, apparently didn’t worsen outcomes by itself. The risk for death from any cause at higher obesity levels was found to depend a lot on related risk factors and comorbidities when the analysis controlled for conditions such as diabetes and hypertension.
The findings suggest an inverse relationship between BMI and all-cause mortality in AFib only for patients with BMI less than about 30. They therefore argue against any “obesity paradox” in AFib that posits consistently better survival with increasing levels of obesity, say researchers, based on their analysis of patients with new-onset AFib in the GARFIELD-AF registry.
“It’s common practice now for clinicians to discuss weight within a clinic setting when they’re talking to their AFib patients,” observed Christian Fielder Camm, BM, BCh, University of Oxford (England), and Royal Berkshire NHS Foundation Trust, Reading, England. So studies suggesting an inverse association between BMI and AFib-related risk can be a concern.
Such studies “seem to suggest that once you’ve got AFib, maintaining a high or very high BMI may in some way be protective – which is contrary to what would seem to make sense and certainly contrary to what our results have shown,” Dr. Camm told this news organization.
“I think that having further evidence now to suggest, actually, that greater BMI is associated with a greater risk of all-cause mortality and heart failure helps reframe that discussion at the physician-patient interaction level more clearly, and ensures that we’re able to talk to our patients appropriately about risks associated with BMI and atrial fibrillation,” said Dr. Camm, who is lead author on the analysis published in Open Heart.
“Obesity is a cause of most cardiovascular diseases, but [these] data would support that being overweight or having mild obesity does not increase the risk,” observed Carl J. Lavie, MD, of the John Ochsner Heart and Vascular Institute, New Orleans, La., and the Ochsner Clinical School at the University of Queensland, Brisbane, Australia.
“At a BMI of 40, it’s very important for them to lose weight for their long-term prognosis,” Dr. Lavie noted, but “at a BMI of 30, the important thing would be to prevent further weight gain. And if they could keep their BMI of 30, they should have a good prognosis. Their prognosis would be particularly good if they didn’t gain weight and put themselves in a more extreme obesity class that is associated with worse risk.”
The current analysis, Dr. Lavie said, “is way better than the AFFIRM study,” which yielded an obesity-paradox report on its patients with AFib about a dozen years ago. “It’s got more data, more numbers, more statistical power,” and breaks BMI into more categories.
That previous analysis based on the influential AFFIRM randomized trial separated its 4,060 patients with AFib into normal (BMI, 18.5-25), overweight (BMI, 25-30), and obese (BMI, > 30) categories, per the convention at the time. It concluded that “obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.”
Bleeding risk on oral anticoagulants
Also noteworthy in the current analysis, variation in BMI didn’t seem to affect mortality or risk for major bleeding or nonhemorrhagic stroke according to choice of oral anticoagulant – whether a new oral anticoagulant (NOAC) or a vitamin K antagonist (VKA).
“We saw that even in the obese and extremely obese group, all-cause mortality was lower in the group taking NOACs, compared with taking warfarin,” Dr. Camm observed, “which goes against the idea that we would need any kind of dose adjustments for increased BMI.”
Indeed, the report notes, use of NOACs, compared with VKA, was associated with a 23% drop in risk for death among patients who were either normal weight or overweight and also in those who were obese or extremely obese.
Those findings “are basically saying that the NOACs look better than warfarin regardless of weight,” agreed Dr. Lavie. “The problem is that the study is not very powered.”
Whereas the benefits of NOACs, compared to VKA, seem similar for patients with a BMI of 30 or 34, compared with a BMI of 23, for example, “none of the studies has many people with 50 BMI.” Many clinicians “feel uncomfortable giving the same dose of NOAC to somebody who has a 60 BMI,” he said. At least with warfarin, “you can check the INR [international normalized ratio].”
The current analysis included 40,482 patients with recently diagnosed AFib and at least one other stroke risk factor from among the registry’s more than 50,000 patients from 35 countries, enrolled from 2010 to 2016. They were followed for 2 years.
The 703 patients with BMI under 18.5 at AFib diagnosis were classified per World Health Organization definitions as underweight; the 13,095 with BMI 18.5-25 as normal weight; the 15,043 with BMI 25-30 as overweight; the 7,560 with BMI 30-35 as obese; and the 4,081 with BMI above 35 as extremely obese. Their ages averaged 71 years, and 55.6% were men.
BMI effects on different outcomes
Relationships between BMI and all-cause mortality and between BMI and new or worsening HF emerged as U-shaped, the risk climbing with both increasing and decreasing BMI. The nadir BMI for risk was about 30 in the case of mortality and about 25 for new or worsening HF.
The all-cause mortality risk rose by 32% for every 5 BMI points lower than a BMI of 30, and by 16% for every 5 BMI points higher than 30, in a partially adjusted analysis. The risk for new or worsening HF rose significantly with increasing but not decreasing BMI, and the reverse was observed for the endpoint of major bleeding.
The effect of BMI on all-cause mortality was “substantially attenuated” when the analysis was further adjusted with “likely mediators of any association between BMI and outcomes,” including hypertension, diabetes, HF, cerebrovascular events, and history of bleeding, Dr. Camm said.
That blunted BMI-mortality relationship, he said, “suggests that a lot of the effect is mediated through relatively traditional risk factors like hypertension and diabetes.”
The 2010 AFFIRM analysis by BMI, Dr. Lavie noted, “didn’t even look at the underweight; they actually threw them out.” Yet, such patients with AFib, who tend to be extremely frail or have chronic diseases or conditions other than the arrhythmia, are common. A take-home of the current study is that “the underweight with atrial fibrillation have a really bad prognosis.”
That message isn’t heard as much, he observed, “but is as important as saying that BMI 30 has the best prognosis. The worst prognosis is with the underweight or the really extreme obese.”
Dr. Camm discloses research funding from the British Heart Foundation. Disclosures for the other authors are in the report. Dr. Lavie has previously disclosed serving as a speaker and consultant for PAI Health and DSM Nutritional Products and is the author of “The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier” (Avery, 2014).
A version of this article first appeared on Medscape.com.
FROM OPEN HEART
Obesity drug shortage triggers frustrations, workarounds
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
Meet a champion climber with type 1 diabetes
Managing type 1 diabetes is never easy. But if you ask 16-year-old climbing star Katie Bone, she’ll tell you that she will never let this disease get in the way of her goals.
“My motto is the same one as Bethany Hamilton’s – the surfer who lost her arm in a shark attack: ‘I don’t need easy, I just need possible,” said Ms. Bone, who lives in Albuquerque and has been a competitive rock climber since she was 8 years old. “That really stuck with me.”
Just watching her compete on NBC’s hit reality show American Ninja Warrior in June is proof of that. Not only did the nationally ranked climber fly through the obstacles with grace and grit, but she proudly showed off her two monitoring devices: a glucose monitor on one arm and a tubeless insulin pump on the other.
“I specifically decided to keep my devices visible when I went on the show,” she said. “It’s part of my life, and I wanted to show that I’m not ashamed to wear medical devices.”
Still, it has been a long journey since Bone was diagnosed in 2017. She was just 11 years old at the time and had recently done a climbing competition when she started feeling ill.
“I didn’t perform well,” she said. “I needed to go to the bathroom a lot and felt really nauseous. Three days later, we ended up in urgent care.”
When her doctor first told her she had diabetes, she started crying.
“My grandma had type 1 and was extremely sick and died from complications,” she said. “That was all I knew about diabetes, and it was scary to think my life could be like that.”
But her outlook brightened when her doctor assured her that she could keep climbing.
“When I was told that I could keep competing, a switch flipped for me and I made a decision that nothing would hold me back,” she says.
But every day isn’t easy.
“It’s sometimes really hard to manage my diabetes during competitions,” she said. “When we climb, for example, we’re not allowed to have our phones, and I manage my [glucose monitor] through my phone. This means accommodations have to be made for me.”
And managing her diabetes can be unpredictable at times.
“If my blood sugar is low or high, I might be put last in a competition,” she said. “That messes up my warm-up and my mental game. It’s a never-ending battle.”
Ultimately, Ms. Bone’s goal is to inspire others and advocate for diabetes awareness. She says she’s been overwhelmed by viewer responses to her appearance on the show.
“I heard from so many parents and kids,” she said. “I want the world to know that wearing a pump on your arm only makes you more amazing.”
She also draws inspiration from others with diabetes.
“Everyone with this disease is a role model for me, since everyone is fighting their own battles,” she said. “Diabetes is different for everyone, and seeing how people can do what they do despite the diagnosis has been incredibly inspiring.”
For now, the rising high school junior plans to continue training and competing.
“My goal is to make the 2024 Olympic climbing team in Paris,” she said. “I’ve always wanted to compete in the Olympics since I was a little kid. Nothing can stop me.”
A version of this article first appeared on WebMD.com.
Managing type 1 diabetes is never easy. But if you ask 16-year-old climbing star Katie Bone, she’ll tell you that she will never let this disease get in the way of her goals.
“My motto is the same one as Bethany Hamilton’s – the surfer who lost her arm in a shark attack: ‘I don’t need easy, I just need possible,” said Ms. Bone, who lives in Albuquerque and has been a competitive rock climber since she was 8 years old. “That really stuck with me.”
Just watching her compete on NBC’s hit reality show American Ninja Warrior in June is proof of that. Not only did the nationally ranked climber fly through the obstacles with grace and grit, but she proudly showed off her two monitoring devices: a glucose monitor on one arm and a tubeless insulin pump on the other.
“I specifically decided to keep my devices visible when I went on the show,” she said. “It’s part of my life, and I wanted to show that I’m not ashamed to wear medical devices.”
Still, it has been a long journey since Bone was diagnosed in 2017. She was just 11 years old at the time and had recently done a climbing competition when she started feeling ill.
“I didn’t perform well,” she said. “I needed to go to the bathroom a lot and felt really nauseous. Three days later, we ended up in urgent care.”
When her doctor first told her she had diabetes, she started crying.
“My grandma had type 1 and was extremely sick and died from complications,” she said. “That was all I knew about diabetes, and it was scary to think my life could be like that.”
But her outlook brightened when her doctor assured her that she could keep climbing.
“When I was told that I could keep competing, a switch flipped for me and I made a decision that nothing would hold me back,” she says.
But every day isn’t easy.
“It’s sometimes really hard to manage my diabetes during competitions,” she said. “When we climb, for example, we’re not allowed to have our phones, and I manage my [glucose monitor] through my phone. This means accommodations have to be made for me.”
And managing her diabetes can be unpredictable at times.
“If my blood sugar is low or high, I might be put last in a competition,” she said. “That messes up my warm-up and my mental game. It’s a never-ending battle.”
Ultimately, Ms. Bone’s goal is to inspire others and advocate for diabetes awareness. She says she’s been overwhelmed by viewer responses to her appearance on the show.
“I heard from so many parents and kids,” she said. “I want the world to know that wearing a pump on your arm only makes you more amazing.”
She also draws inspiration from others with diabetes.
“Everyone with this disease is a role model for me, since everyone is fighting their own battles,” she said. “Diabetes is different for everyone, and seeing how people can do what they do despite the diagnosis has been incredibly inspiring.”
For now, the rising high school junior plans to continue training and competing.
“My goal is to make the 2024 Olympic climbing team in Paris,” she said. “I’ve always wanted to compete in the Olympics since I was a little kid. Nothing can stop me.”
A version of this article first appeared on WebMD.com.
Managing type 1 diabetes is never easy. But if you ask 16-year-old climbing star Katie Bone, she’ll tell you that she will never let this disease get in the way of her goals.
“My motto is the same one as Bethany Hamilton’s – the surfer who lost her arm in a shark attack: ‘I don’t need easy, I just need possible,” said Ms. Bone, who lives in Albuquerque and has been a competitive rock climber since she was 8 years old. “That really stuck with me.”
Just watching her compete on NBC’s hit reality show American Ninja Warrior in June is proof of that. Not only did the nationally ranked climber fly through the obstacles with grace and grit, but she proudly showed off her two monitoring devices: a glucose monitor on one arm and a tubeless insulin pump on the other.
“I specifically decided to keep my devices visible when I went on the show,” she said. “It’s part of my life, and I wanted to show that I’m not ashamed to wear medical devices.”
Still, it has been a long journey since Bone was diagnosed in 2017. She was just 11 years old at the time and had recently done a climbing competition when she started feeling ill.
“I didn’t perform well,” she said. “I needed to go to the bathroom a lot and felt really nauseous. Three days later, we ended up in urgent care.”
When her doctor first told her she had diabetes, she started crying.
“My grandma had type 1 and was extremely sick and died from complications,” she said. “That was all I knew about diabetes, and it was scary to think my life could be like that.”
But her outlook brightened when her doctor assured her that she could keep climbing.
“When I was told that I could keep competing, a switch flipped for me and I made a decision that nothing would hold me back,” she says.
But every day isn’t easy.
“It’s sometimes really hard to manage my diabetes during competitions,” she said. “When we climb, for example, we’re not allowed to have our phones, and I manage my [glucose monitor] through my phone. This means accommodations have to be made for me.”
And managing her diabetes can be unpredictable at times.
“If my blood sugar is low or high, I might be put last in a competition,” she said. “That messes up my warm-up and my mental game. It’s a never-ending battle.”
Ultimately, Ms. Bone’s goal is to inspire others and advocate for diabetes awareness. She says she’s been overwhelmed by viewer responses to her appearance on the show.
“I heard from so many parents and kids,” she said. “I want the world to know that wearing a pump on your arm only makes you more amazing.”
She also draws inspiration from others with diabetes.
“Everyone with this disease is a role model for me, since everyone is fighting their own battles,” she said. “Diabetes is different for everyone, and seeing how people can do what they do despite the diagnosis has been incredibly inspiring.”
For now, the rising high school junior plans to continue training and competing.
“My goal is to make the 2024 Olympic climbing team in Paris,” she said. “I’ve always wanted to compete in the Olympics since I was a little kid. Nothing can stop me.”
A version of this article first appeared on WebMD.com.
Short walks after meals can cut diabetes risk
Taking a brief walk after eating can help lower the risk of type 2 diabetes, according to a recent study published in Sports Medicine (2022 Aug;52:1765-87).
Light walking after a meal – even for 2-5 minutes – can reduce blood sugar and insulin levels, the researchers found.
Blood sugar levels spike after eating, and the insulin produced to control them can lead to diabetes and cardiovascular issues, the researchers explained.
“With standing and walking, there are contractions of your muscles” that use glucose and lower blood sugar levels, Aidan Buffey, the lead study author and a PhD student in physical education and sport sciences at the University of Limerick (Ireland), told The Times.
“If you can do physical activity before the glucose peak, typically 60-90 minutes [after eating], that is when you’re going to have the benefit of not having the glucose spike,” he said.
Mr. Buffey and colleagues looked at seven studies to understand what would happen if you used standing or easy walking to interrupt prolonged sitting.
In five of the studies, none of the participants had prediabetes or type 2 diabetes. The other two studies included people with and without diabetes. The people in the studies were asked to either stand or walk for 2-5 minutes every 20-30 minutes over the course of a full day.
All seven studies showed that standing after a meal is better than sitting, and taking a short walk offered even better health benefits. Those who stood up for a short period of time after a meal had improved blood sugar levels but not insulin, while those who took a brief walk after a meal had lower blood sugar and insulin levels. Those who walked also had blood sugar levels that rose and fell more gradually, which is critical for managing diabetes.
Going for a walk, doing housework, or finding other ways to move your body within 60-90 minutes after eating could offer the best results, the study authors concluded.
These “mini-walks” could also be useful during the workday to break up prolonged periods of sitting at a desk.
“People are not going to get up and run on a treadmill or run around the office,” Mr. Buffey told The New York Times.
But making mini-walks a normal thing during the workday could be easy and acceptable at the office, he said. Even if people can’t take walks, standing up will help somewhat.
“Each small thing you do will have benefits, even if it is a small step,” Kershaw Patel, MD, a preventive cardiologist at Houston Methodist Hospital, told the newspaper. Dr. Patel wasn’t involved with the study.
“It’s a gradual effect of more activity, better health,” he said. “Each incremental step, each incremental stand or brisk walk appears to have a benefit.”
A version of this article first appeared on WebMD.com.
Taking a brief walk after eating can help lower the risk of type 2 diabetes, according to a recent study published in Sports Medicine (2022 Aug;52:1765-87).
Light walking after a meal – even for 2-5 minutes – can reduce blood sugar and insulin levels, the researchers found.
Blood sugar levels spike after eating, and the insulin produced to control them can lead to diabetes and cardiovascular issues, the researchers explained.
“With standing and walking, there are contractions of your muscles” that use glucose and lower blood sugar levels, Aidan Buffey, the lead study author and a PhD student in physical education and sport sciences at the University of Limerick (Ireland), told The Times.
“If you can do physical activity before the glucose peak, typically 60-90 minutes [after eating], that is when you’re going to have the benefit of not having the glucose spike,” he said.
Mr. Buffey and colleagues looked at seven studies to understand what would happen if you used standing or easy walking to interrupt prolonged sitting.
In five of the studies, none of the participants had prediabetes or type 2 diabetes. The other two studies included people with and without diabetes. The people in the studies were asked to either stand or walk for 2-5 minutes every 20-30 minutes over the course of a full day.
All seven studies showed that standing after a meal is better than sitting, and taking a short walk offered even better health benefits. Those who stood up for a short period of time after a meal had improved blood sugar levels but not insulin, while those who took a brief walk after a meal had lower blood sugar and insulin levels. Those who walked also had blood sugar levels that rose and fell more gradually, which is critical for managing diabetes.
Going for a walk, doing housework, or finding other ways to move your body within 60-90 minutes after eating could offer the best results, the study authors concluded.
These “mini-walks” could also be useful during the workday to break up prolonged periods of sitting at a desk.
“People are not going to get up and run on a treadmill or run around the office,” Mr. Buffey told The New York Times.
But making mini-walks a normal thing during the workday could be easy and acceptable at the office, he said. Even if people can’t take walks, standing up will help somewhat.
“Each small thing you do will have benefits, even if it is a small step,” Kershaw Patel, MD, a preventive cardiologist at Houston Methodist Hospital, told the newspaper. Dr. Patel wasn’t involved with the study.
“It’s a gradual effect of more activity, better health,” he said. “Each incremental step, each incremental stand or brisk walk appears to have a benefit.”
A version of this article first appeared on WebMD.com.
Taking a brief walk after eating can help lower the risk of type 2 diabetes, according to a recent study published in Sports Medicine (2022 Aug;52:1765-87).
Light walking after a meal – even for 2-5 minutes – can reduce blood sugar and insulin levels, the researchers found.
Blood sugar levels spike after eating, and the insulin produced to control them can lead to diabetes and cardiovascular issues, the researchers explained.
“With standing and walking, there are contractions of your muscles” that use glucose and lower blood sugar levels, Aidan Buffey, the lead study author and a PhD student in physical education and sport sciences at the University of Limerick (Ireland), told The Times.
“If you can do physical activity before the glucose peak, typically 60-90 minutes [after eating], that is when you’re going to have the benefit of not having the glucose spike,” he said.
Mr. Buffey and colleagues looked at seven studies to understand what would happen if you used standing or easy walking to interrupt prolonged sitting.
In five of the studies, none of the participants had prediabetes or type 2 diabetes. The other two studies included people with and without diabetes. The people in the studies were asked to either stand or walk for 2-5 minutes every 20-30 minutes over the course of a full day.
All seven studies showed that standing after a meal is better than sitting, and taking a short walk offered even better health benefits. Those who stood up for a short period of time after a meal had improved blood sugar levels but not insulin, while those who took a brief walk after a meal had lower blood sugar and insulin levels. Those who walked also had blood sugar levels that rose and fell more gradually, which is critical for managing diabetes.
Going for a walk, doing housework, or finding other ways to move your body within 60-90 minutes after eating could offer the best results, the study authors concluded.
These “mini-walks” could also be useful during the workday to break up prolonged periods of sitting at a desk.
“People are not going to get up and run on a treadmill or run around the office,” Mr. Buffey told The New York Times.
But making mini-walks a normal thing during the workday could be easy and acceptable at the office, he said. Even if people can’t take walks, standing up will help somewhat.
“Each small thing you do will have benefits, even if it is a small step,” Kershaw Patel, MD, a preventive cardiologist at Houston Methodist Hospital, told the newspaper. Dr. Patel wasn’t involved with the study.
“It’s a gradual effect of more activity, better health,” he said. “Each incremental step, each incremental stand or brisk walk appears to have a benefit.”
A version of this article first appeared on WebMD.com.
Is prostasin a clue to diabetes/cancer link?
People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.
The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.
“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.
“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”
He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”
Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).
During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
Potential diabetes-cancer ‘interaction’
The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).
Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”
He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”
Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”
Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.
This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”
The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.
“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”
Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”
Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.
The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.
“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.
“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”
He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”
Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).
During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
Potential diabetes-cancer ‘interaction’
The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).
Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”
He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”
Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”
Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.
This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”
The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.
“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”
Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”
Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.
The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.
“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.
“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”
He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”
Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).
During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
Potential diabetes-cancer ‘interaction’
The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).
Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”
He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”
Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”
Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.
This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”
The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.
“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”
Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”
Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
FROM DIABETOLOGIA
Neuropathy drives hypoglycemia cluelessness in T1D
Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.
Key takeaways
- In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
- Diabetes distress and fear of hypoglycemia are common in people with IAH.
Why this matters
- Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
- This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
- People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
- The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.
Study design
- The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
- The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .
Key results
- DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
- Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
- The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
- Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
- All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
- Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
- Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.
Limitations
- The study used a cross-sectional design, which is not suited to making causal inferences.
- The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
- The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.
Disclosures
- The study received no commercial funding.
- The authors have disclosed no relevant financial relationships.
This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.
A version of this article first appeared on Medscape.com.
Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.
Key takeaways
- In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
- Diabetes distress and fear of hypoglycemia are common in people with IAH.
Why this matters
- Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
- This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
- People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
- The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.
Study design
- The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
- The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .
Key results
- DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
- Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
- The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
- Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
- All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
- Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
- Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.
Limitations
- The study used a cross-sectional design, which is not suited to making causal inferences.
- The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
- The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.
Disclosures
- The study received no commercial funding.
- The authors have disclosed no relevant financial relationships.
This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.
A version of this article first appeared on Medscape.com.
Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.
Key takeaways
- In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
- Diabetes distress and fear of hypoglycemia are common in people with IAH.
Why this matters
- Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
- This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
- People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
- The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.
Study design
- The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
- The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .
Key results
- DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
- Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
- The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
- Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
- All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
- Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
- Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.
Limitations
- The study used a cross-sectional design, which is not suited to making causal inferences.
- The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
- The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.
Disclosures
- The study received no commercial funding.
- The authors have disclosed no relevant financial relationships.
This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.
A version of this article first appeared on Medscape.com.