User login
‘Striking’ benefit of lipid lowering in primary prevention
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
SAN DIEGO – two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.
The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.
This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.
Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.
“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview.
“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.
But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated.
“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed.
Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.”
“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
‘Wake-up call’
He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”
Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels.
“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”
Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.
He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years.
“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.
“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.
Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.
Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”
And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
Greater benefit in primary prevention?
In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed impressive reductions.
The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.
Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.
“It may seem paradoxical, but there is actually some history that this may be the case,” he said.
He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.
He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.
“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.
Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.
“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”
He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
Editorial cautious
In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.
Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.
Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.
“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.
A version of this article first appeared on Medscape.com.
AT ADA 2023
Does ‘skeletal age’ describe fracture impact on mortality?
Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.
The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.
Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.
In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.
They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.
The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.
For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.
The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.
The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.
However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”
Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.
Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).
While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.
Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.
A version of this article first appeared on Medscape.com.
Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.
The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.
Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.
In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.
They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.
The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.
For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.
The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.
The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.
However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”
Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.
Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).
While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.
Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.
A version of this article first appeared on Medscape.com.
Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.
The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.
Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.
In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.
They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.
The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.
For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.
The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.
The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.
However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”
Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.
Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).
While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.
Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.
A version of this article first appeared on Medscape.com.
Scripts surge for desiccated thyroid extract to treat hypothyroidism
new research has found.
Nationwide MarketScan claims data reveal that, among first-time thyroid hormone prescriptions, those for DTE rose from 5.4% in 2010 to 10.2% in 2020. At the same time, prescriptions for first-line levothyroxine dropped from 91.8% to 87.2%. Prescriptions for liothyronine (LT3), primarily in combination with levothyroxine, remained at about 2% throughout the decade.
The nonlevothyroxine therapies were more commonly prescribed in the West and Southwestern United States, while levothyroxine monotherapy was more frequent in the Northwest and upper Midwest, and also in states with higher densities of primary care physicians and endocrinologists.
The magnitude of this shift in first-line treatment was unexpected.
“We were frankly quite surprised to see that difference in just 10 years,” lead author Matthew Ettleson, MD, of the University of Chicago, said in an interview.
Asked to comment, session moderator Elizabeth N. Pearce, MD, professor of medicine at Boston University Medical Center, said she also found the dramatic shift to DTE surprising.
“It’s unclear why since there hasn’t been a shift in the science or in the guidelines over the last decade. ... I think we need to understand better what is driving this, who the patients are who are seeking it out, and which providers are the primary drivers of these prescriptions,” she said.
Dr. Ettleson presented the findings at the annual meeting of the Endocrine Society. The results were simultaneously published in the Journal of Clinical Endocrinology and Metabolism.
Why the increase in desiccated thyroid extract?
Current guidelines by the American Thyroid Association recommend levothyroxine, a synthetic form of thyroxine (T4) monotherapy, as the standard of care for treating hypothyroidism. However, approximately 10%-20% of levothyroxine-treated patients report bothersome symptoms despite normalization of thyroid-stimulating hormone (TSH) levels.
In 2021, the ATA, along with European and British thyroid societies, issued a consensus statement noting that new trials of triiodothyronine (T3)/T4 combination therapy were “justified.”
However, the MarketScan data were gathered before that statement came out, which doesn’t mention desiccated thyroid extract, “so that’s a bit of a head-scratcher,” Ettleson said.
He said one possibility may be the existence of online materials saying negative things about levothyroxine, so that “people who are just learning about hypothyroidism might already be primed to think about alternative treatments.” Moreover, some patients may view DTE as more “natural” than levothyroxine.
Dr. Ettleson also noted that the distinct geographic variation “didn’t seem random. ... So not only was there a doubling overall but there’s a variation in practice patterns across the country. I don’t have an explanation for that, but I think it’s important to recognize in the medical community that there are these big differences.”
Endocrinologists not as keen to prescribe DTE or T3
Residence in a state with higher endocrinologist density (3.0/100,000 population) was associated with a decreased likelihood of receiving T3 (adjusted odds ratio, 0.33; P < .001) or DTE therapy (aOR, 0.18; P < .001).
Residence in large central metro zones was associated with an increased likelihood of receiving T3 (aOR, 1.32; P < .001) or DTE therapy (aOR, 1.05; P < .008, respectively).
Dr. Pearce observed: “I don’t see DTE in Boston. It’s mostly in the South and Southwest.”
She said she doubted that endocrinologists were the primary prescribers of DTE, as many endocrinologists are “wary” of the pig thyroid–derived product because its T4 to T3 ratio is about 4:1, in contrast to the ratio in humans of 13-14:1.
Thus, DTE contains a much higher proportion of the active hormone T3. It is also much shorter acting, with a half-life of a few hours, compared to a few days for T4, she explained.
“We don’t really know what long-term safety effects are but it’s probably a less physiologic way of dosing thyroid hormone than ... either levothyroxine or levothyroxine in combination with a lower T3 proportion,” she said.
Just trying to understand
Dr. Ettleson emphasized that the goal of his research wasn’t to reverse the trend but to better understand it.
Nonetheless, he also noted, “now that we know there are more patients taking DTE, we need to start looking at rates of atrial fibrillation, fracture, heart failure, and other possible outcomes in this population and compare them with levothyroxine and nonthyroid populations to make sure that it is as safe as levothyroxine.”
“There are no data to suggest increased risk, especially if TSH is monitored and stays in the normal range, but there’s very little data for over 5 or 10 years on DTE-treated patients. We need the data,” he emphasized.
Meanwhile, he’s working on a survey of endocrinologists and non-endocrinologists to ask if they’ve prescribed DTE, and if so, why, and whether it’s because patients asked for it. “There’s a lot more work to be done, but I think it’s exciting. It’s important to see how patients are being treated in the real world ... and understand why it’s happening and what the outcomes are.”
Dr. Ettleson and Dr. Pearce have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research has found.
Nationwide MarketScan claims data reveal that, among first-time thyroid hormone prescriptions, those for DTE rose from 5.4% in 2010 to 10.2% in 2020. At the same time, prescriptions for first-line levothyroxine dropped from 91.8% to 87.2%. Prescriptions for liothyronine (LT3), primarily in combination with levothyroxine, remained at about 2% throughout the decade.
The nonlevothyroxine therapies were more commonly prescribed in the West and Southwestern United States, while levothyroxine monotherapy was more frequent in the Northwest and upper Midwest, and also in states with higher densities of primary care physicians and endocrinologists.
The magnitude of this shift in first-line treatment was unexpected.
“We were frankly quite surprised to see that difference in just 10 years,” lead author Matthew Ettleson, MD, of the University of Chicago, said in an interview.
Asked to comment, session moderator Elizabeth N. Pearce, MD, professor of medicine at Boston University Medical Center, said she also found the dramatic shift to DTE surprising.
“It’s unclear why since there hasn’t been a shift in the science or in the guidelines over the last decade. ... I think we need to understand better what is driving this, who the patients are who are seeking it out, and which providers are the primary drivers of these prescriptions,” she said.
Dr. Ettleson presented the findings at the annual meeting of the Endocrine Society. The results were simultaneously published in the Journal of Clinical Endocrinology and Metabolism.
Why the increase in desiccated thyroid extract?
Current guidelines by the American Thyroid Association recommend levothyroxine, a synthetic form of thyroxine (T4) monotherapy, as the standard of care for treating hypothyroidism. However, approximately 10%-20% of levothyroxine-treated patients report bothersome symptoms despite normalization of thyroid-stimulating hormone (TSH) levels.
In 2021, the ATA, along with European and British thyroid societies, issued a consensus statement noting that new trials of triiodothyronine (T3)/T4 combination therapy were “justified.”
However, the MarketScan data were gathered before that statement came out, which doesn’t mention desiccated thyroid extract, “so that’s a bit of a head-scratcher,” Ettleson said.
He said one possibility may be the existence of online materials saying negative things about levothyroxine, so that “people who are just learning about hypothyroidism might already be primed to think about alternative treatments.” Moreover, some patients may view DTE as more “natural” than levothyroxine.
Dr. Ettleson also noted that the distinct geographic variation “didn’t seem random. ... So not only was there a doubling overall but there’s a variation in practice patterns across the country. I don’t have an explanation for that, but I think it’s important to recognize in the medical community that there are these big differences.”
Endocrinologists not as keen to prescribe DTE or T3
Residence in a state with higher endocrinologist density (3.0/100,000 population) was associated with a decreased likelihood of receiving T3 (adjusted odds ratio, 0.33; P < .001) or DTE therapy (aOR, 0.18; P < .001).
Residence in large central metro zones was associated with an increased likelihood of receiving T3 (aOR, 1.32; P < .001) or DTE therapy (aOR, 1.05; P < .008, respectively).
Dr. Pearce observed: “I don’t see DTE in Boston. It’s mostly in the South and Southwest.”
She said she doubted that endocrinologists were the primary prescribers of DTE, as many endocrinologists are “wary” of the pig thyroid–derived product because its T4 to T3 ratio is about 4:1, in contrast to the ratio in humans of 13-14:1.
Thus, DTE contains a much higher proportion of the active hormone T3. It is also much shorter acting, with a half-life of a few hours, compared to a few days for T4, she explained.
“We don’t really know what long-term safety effects are but it’s probably a less physiologic way of dosing thyroid hormone than ... either levothyroxine or levothyroxine in combination with a lower T3 proportion,” she said.
Just trying to understand
Dr. Ettleson emphasized that the goal of his research wasn’t to reverse the trend but to better understand it.
Nonetheless, he also noted, “now that we know there are more patients taking DTE, we need to start looking at rates of atrial fibrillation, fracture, heart failure, and other possible outcomes in this population and compare them with levothyroxine and nonthyroid populations to make sure that it is as safe as levothyroxine.”
“There are no data to suggest increased risk, especially if TSH is monitored and stays in the normal range, but there’s very little data for over 5 or 10 years on DTE-treated patients. We need the data,” he emphasized.
Meanwhile, he’s working on a survey of endocrinologists and non-endocrinologists to ask if they’ve prescribed DTE, and if so, why, and whether it’s because patients asked for it. “There’s a lot more work to be done, but I think it’s exciting. It’s important to see how patients are being treated in the real world ... and understand why it’s happening and what the outcomes are.”
Dr. Ettleson and Dr. Pearce have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research has found.
Nationwide MarketScan claims data reveal that, among first-time thyroid hormone prescriptions, those for DTE rose from 5.4% in 2010 to 10.2% in 2020. At the same time, prescriptions for first-line levothyroxine dropped from 91.8% to 87.2%. Prescriptions for liothyronine (LT3), primarily in combination with levothyroxine, remained at about 2% throughout the decade.
The nonlevothyroxine therapies were more commonly prescribed in the West and Southwestern United States, while levothyroxine monotherapy was more frequent in the Northwest and upper Midwest, and also in states with higher densities of primary care physicians and endocrinologists.
The magnitude of this shift in first-line treatment was unexpected.
“We were frankly quite surprised to see that difference in just 10 years,” lead author Matthew Ettleson, MD, of the University of Chicago, said in an interview.
Asked to comment, session moderator Elizabeth N. Pearce, MD, professor of medicine at Boston University Medical Center, said she also found the dramatic shift to DTE surprising.
“It’s unclear why since there hasn’t been a shift in the science or in the guidelines over the last decade. ... I think we need to understand better what is driving this, who the patients are who are seeking it out, and which providers are the primary drivers of these prescriptions,” she said.
Dr. Ettleson presented the findings at the annual meeting of the Endocrine Society. The results were simultaneously published in the Journal of Clinical Endocrinology and Metabolism.
Why the increase in desiccated thyroid extract?
Current guidelines by the American Thyroid Association recommend levothyroxine, a synthetic form of thyroxine (T4) monotherapy, as the standard of care for treating hypothyroidism. However, approximately 10%-20% of levothyroxine-treated patients report bothersome symptoms despite normalization of thyroid-stimulating hormone (TSH) levels.
In 2021, the ATA, along with European and British thyroid societies, issued a consensus statement noting that new trials of triiodothyronine (T3)/T4 combination therapy were “justified.”
However, the MarketScan data were gathered before that statement came out, which doesn’t mention desiccated thyroid extract, “so that’s a bit of a head-scratcher,” Ettleson said.
He said one possibility may be the existence of online materials saying negative things about levothyroxine, so that “people who are just learning about hypothyroidism might already be primed to think about alternative treatments.” Moreover, some patients may view DTE as more “natural” than levothyroxine.
Dr. Ettleson also noted that the distinct geographic variation “didn’t seem random. ... So not only was there a doubling overall but there’s a variation in practice patterns across the country. I don’t have an explanation for that, but I think it’s important to recognize in the medical community that there are these big differences.”
Endocrinologists not as keen to prescribe DTE or T3
Residence in a state with higher endocrinologist density (3.0/100,000 population) was associated with a decreased likelihood of receiving T3 (adjusted odds ratio, 0.33; P < .001) or DTE therapy (aOR, 0.18; P < .001).
Residence in large central metro zones was associated with an increased likelihood of receiving T3 (aOR, 1.32; P < .001) or DTE therapy (aOR, 1.05; P < .008, respectively).
Dr. Pearce observed: “I don’t see DTE in Boston. It’s mostly in the South and Southwest.”
She said she doubted that endocrinologists were the primary prescribers of DTE, as many endocrinologists are “wary” of the pig thyroid–derived product because its T4 to T3 ratio is about 4:1, in contrast to the ratio in humans of 13-14:1.
Thus, DTE contains a much higher proportion of the active hormone T3. It is also much shorter acting, with a half-life of a few hours, compared to a few days for T4, she explained.
“We don’t really know what long-term safety effects are but it’s probably a less physiologic way of dosing thyroid hormone than ... either levothyroxine or levothyroxine in combination with a lower T3 proportion,” she said.
Just trying to understand
Dr. Ettleson emphasized that the goal of his research wasn’t to reverse the trend but to better understand it.
Nonetheless, he also noted, “now that we know there are more patients taking DTE, we need to start looking at rates of atrial fibrillation, fracture, heart failure, and other possible outcomes in this population and compare them with levothyroxine and nonthyroid populations to make sure that it is as safe as levothyroxine.”
“There are no data to suggest increased risk, especially if TSH is monitored and stays in the normal range, but there’s very little data for over 5 or 10 years on DTE-treated patients. We need the data,” he emphasized.
Meanwhile, he’s working on a survey of endocrinologists and non-endocrinologists to ask if they’ve prescribed DTE, and if so, why, and whether it’s because patients asked for it. “There’s a lot more work to be done, but I think it’s exciting. It’s important to see how patients are being treated in the real world ... and understand why it’s happening and what the outcomes are.”
Dr. Ettleson and Dr. Pearce have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ENDO 2023
A ‘one-stop shop’: New guidance on hormones and aging
The idea of the statement “is to be complete, but also to clarify some misunderstandings. ...We tried to be very clear in the language about what we know, where we can go, where we shouldn’t go, and what we still need to learn,” statement coauthor Cynthia A. Stuenkel, MD, of the University of California, San Diego, said in an interview.
The document is divided into nine parts or axes: growth hormone, adrenal, ovarian, testicular, thyroid, osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism. Each section covers natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, bulleted “key points,” and research gaps.
“Hormones and Aging: An Endocrine Society Scientific Statement” was presented at the annual meeting of the Endocrine Society and published online in the Journal of Clinical Endocrinology & Metabolism.
During a press briefing, writing group chair Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia, said the goal is to “provide a really concise summary across each of these areas. ... There are multiple hormonal changes that occur with age, so we really couldn’t limit ourselves to just one gland or the few that we commonly think about. We wanted to cover all the axes.”
The statement tackles several controversial areas, including hormone therapy for menopausal symptoms in women and hypogonadal symptoms in men, diabetes treatment goals in older adults, distinguishing between age-associated changes in thyroid function and early hypothyroidism, and vitamin D supplementation in older adults.
“Hormones have these almost mythical qualities to some people. ... ‘If I just had my hormones back the way they were, it would all work out.’ What we want to do is make sure that patients are being treated appropriately and that their symptoms are being heard and managed and ascribed to the appropriate problems and not necessarily to hormonal problems when they are not. ... Part of what we need to do is [provide] the evidence that we have, which includes evidence of when not to prescribe as well as [when] to prescribe,” Dr. Cappola said.
Not designed to be read all at once
In the menopause section, for example, one “key point” is that menopausal symptoms are common, vary in degree and bother, and can be effectively treated with a variety of therapies proven effective in randomized clinical trials. Another key point is that menopausal hormone therapy is safest for women who are younger than 60 years and less than 10 years since starting menopause.
“It’s almost 20 years since the original Women’s Health Initiative, and that led to an incredible falloff of prescribing hormone therapy and a falloff in teaching of our students, residents, fellows, and practitioners about [menopausal] hormone therapy. ... Hopefully, by issuing this kind of aging statement it gets people to read, think, and learn more. And, hopefully, we can improve the education of physicians. ... Menopause is a universal experience. Clinicians should know about it,” noted Dr. Stuenkel, who chaired the menopause section writing panel.
In the type 2 diabetes section, in the bullet points it is noted that oral glucose tolerance testing may reveal abnormal glucose status in older adults that are not picked up with hemoglobin A1c or fasting glucose levels and that glycemic targets should be individualized.
Asked to comment on the statement, Michele Bellantoni, MD, said: “This was a huge undertaking because there are so many areas of expertise here. I thought they did a very good job of reviewing the literature and showing each of the different hormonal axes. ... It’s a good go-to review.”
“I thought it was a very good attempt to catalog and provide opportunities for policy, and particularly at [the National Institutes of Health], as they look at funding to show where are these gaps and to support appropriate research. I think the most important aspect to come of this is identifying research gaps for funding opportunities. I very much support that,” noted Dr. Bellantoni, who is clinical director of the division of geriatric medicine at Johns Hopkins University, Baltimore.
However, she also said that the 40-page document might be a bit much for busy clinicians, despite the bullet points at the end of each section.
“I would love to see an editorial that puts into perspective the take-home messages or a subsequent article that distills this into every day practice of care of older adults, both preventative and treatment care. ... I think that would be so useful.”
During the briefing, Dr. Cappola noted that the document need not be read all at once.
“It ended up being a large document, but you should not be intimidated by it because each section is only about 2,000 words. So, it’s really a kind of one-stop shop to be able to look across all these axes at once. We also wanted people to think about the common themes that occur across all these axes when considering what’s going on right now and for future research,” she said.
Dr. Stuenkel, Dr. Cappola, and Dr. Bellantoni reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The idea of the statement “is to be complete, but also to clarify some misunderstandings. ...We tried to be very clear in the language about what we know, where we can go, where we shouldn’t go, and what we still need to learn,” statement coauthor Cynthia A. Stuenkel, MD, of the University of California, San Diego, said in an interview.
The document is divided into nine parts or axes: growth hormone, adrenal, ovarian, testicular, thyroid, osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism. Each section covers natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, bulleted “key points,” and research gaps.
“Hormones and Aging: An Endocrine Society Scientific Statement” was presented at the annual meeting of the Endocrine Society and published online in the Journal of Clinical Endocrinology & Metabolism.
During a press briefing, writing group chair Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia, said the goal is to “provide a really concise summary across each of these areas. ... There are multiple hormonal changes that occur with age, so we really couldn’t limit ourselves to just one gland or the few that we commonly think about. We wanted to cover all the axes.”
The statement tackles several controversial areas, including hormone therapy for menopausal symptoms in women and hypogonadal symptoms in men, diabetes treatment goals in older adults, distinguishing between age-associated changes in thyroid function and early hypothyroidism, and vitamin D supplementation in older adults.
“Hormones have these almost mythical qualities to some people. ... ‘If I just had my hormones back the way they were, it would all work out.’ What we want to do is make sure that patients are being treated appropriately and that their symptoms are being heard and managed and ascribed to the appropriate problems and not necessarily to hormonal problems when they are not. ... Part of what we need to do is [provide] the evidence that we have, which includes evidence of when not to prescribe as well as [when] to prescribe,” Dr. Cappola said.
Not designed to be read all at once
In the menopause section, for example, one “key point” is that menopausal symptoms are common, vary in degree and bother, and can be effectively treated with a variety of therapies proven effective in randomized clinical trials. Another key point is that menopausal hormone therapy is safest for women who are younger than 60 years and less than 10 years since starting menopause.
“It’s almost 20 years since the original Women’s Health Initiative, and that led to an incredible falloff of prescribing hormone therapy and a falloff in teaching of our students, residents, fellows, and practitioners about [menopausal] hormone therapy. ... Hopefully, by issuing this kind of aging statement it gets people to read, think, and learn more. And, hopefully, we can improve the education of physicians. ... Menopause is a universal experience. Clinicians should know about it,” noted Dr. Stuenkel, who chaired the menopause section writing panel.
In the type 2 diabetes section, in the bullet points it is noted that oral glucose tolerance testing may reveal abnormal glucose status in older adults that are not picked up with hemoglobin A1c or fasting glucose levels and that glycemic targets should be individualized.
Asked to comment on the statement, Michele Bellantoni, MD, said: “This was a huge undertaking because there are so many areas of expertise here. I thought they did a very good job of reviewing the literature and showing each of the different hormonal axes. ... It’s a good go-to review.”
“I thought it was a very good attempt to catalog and provide opportunities for policy, and particularly at [the National Institutes of Health], as they look at funding to show where are these gaps and to support appropriate research. I think the most important aspect to come of this is identifying research gaps for funding opportunities. I very much support that,” noted Dr. Bellantoni, who is clinical director of the division of geriatric medicine at Johns Hopkins University, Baltimore.
However, she also said that the 40-page document might be a bit much for busy clinicians, despite the bullet points at the end of each section.
“I would love to see an editorial that puts into perspective the take-home messages or a subsequent article that distills this into every day practice of care of older adults, both preventative and treatment care. ... I think that would be so useful.”
During the briefing, Dr. Cappola noted that the document need not be read all at once.
“It ended up being a large document, but you should not be intimidated by it because each section is only about 2,000 words. So, it’s really a kind of one-stop shop to be able to look across all these axes at once. We also wanted people to think about the common themes that occur across all these axes when considering what’s going on right now and for future research,” she said.
Dr. Stuenkel, Dr. Cappola, and Dr. Bellantoni reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The idea of the statement “is to be complete, but also to clarify some misunderstandings. ...We tried to be very clear in the language about what we know, where we can go, where we shouldn’t go, and what we still need to learn,” statement coauthor Cynthia A. Stuenkel, MD, of the University of California, San Diego, said in an interview.
The document is divided into nine parts or axes: growth hormone, adrenal, ovarian, testicular, thyroid, osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism. Each section covers natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, bulleted “key points,” and research gaps.
“Hormones and Aging: An Endocrine Society Scientific Statement” was presented at the annual meeting of the Endocrine Society and published online in the Journal of Clinical Endocrinology & Metabolism.
During a press briefing, writing group chair Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia, said the goal is to “provide a really concise summary across each of these areas. ... There are multiple hormonal changes that occur with age, so we really couldn’t limit ourselves to just one gland or the few that we commonly think about. We wanted to cover all the axes.”
The statement tackles several controversial areas, including hormone therapy for menopausal symptoms in women and hypogonadal symptoms in men, diabetes treatment goals in older adults, distinguishing between age-associated changes in thyroid function and early hypothyroidism, and vitamin D supplementation in older adults.
“Hormones have these almost mythical qualities to some people. ... ‘If I just had my hormones back the way they were, it would all work out.’ What we want to do is make sure that patients are being treated appropriately and that their symptoms are being heard and managed and ascribed to the appropriate problems and not necessarily to hormonal problems when they are not. ... Part of what we need to do is [provide] the evidence that we have, which includes evidence of when not to prescribe as well as [when] to prescribe,” Dr. Cappola said.
Not designed to be read all at once
In the menopause section, for example, one “key point” is that menopausal symptoms are common, vary in degree and bother, and can be effectively treated with a variety of therapies proven effective in randomized clinical trials. Another key point is that menopausal hormone therapy is safest for women who are younger than 60 years and less than 10 years since starting menopause.
“It’s almost 20 years since the original Women’s Health Initiative, and that led to an incredible falloff of prescribing hormone therapy and a falloff in teaching of our students, residents, fellows, and practitioners about [menopausal] hormone therapy. ... Hopefully, by issuing this kind of aging statement it gets people to read, think, and learn more. And, hopefully, we can improve the education of physicians. ... Menopause is a universal experience. Clinicians should know about it,” noted Dr. Stuenkel, who chaired the menopause section writing panel.
In the type 2 diabetes section, in the bullet points it is noted that oral glucose tolerance testing may reveal abnormal glucose status in older adults that are not picked up with hemoglobin A1c or fasting glucose levels and that glycemic targets should be individualized.
Asked to comment on the statement, Michele Bellantoni, MD, said: “This was a huge undertaking because there are so many areas of expertise here. I thought they did a very good job of reviewing the literature and showing each of the different hormonal axes. ... It’s a good go-to review.”
“I thought it was a very good attempt to catalog and provide opportunities for policy, and particularly at [the National Institutes of Health], as they look at funding to show where are these gaps and to support appropriate research. I think the most important aspect to come of this is identifying research gaps for funding opportunities. I very much support that,” noted Dr. Bellantoni, who is clinical director of the division of geriatric medicine at Johns Hopkins University, Baltimore.
However, she also said that the 40-page document might be a bit much for busy clinicians, despite the bullet points at the end of each section.
“I would love to see an editorial that puts into perspective the take-home messages or a subsequent article that distills this into every day practice of care of older adults, both preventative and treatment care. ... I think that would be so useful.”
During the briefing, Dr. Cappola noted that the document need not be read all at once.
“It ended up being a large document, but you should not be intimidated by it because each section is only about 2,000 words. So, it’s really a kind of one-stop shop to be able to look across all these axes at once. We also wanted people to think about the common themes that occur across all these axes when considering what’s going on right now and for future research,” she said.
Dr. Stuenkel, Dr. Cappola, and Dr. Bellantoni reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ENDO 2023
BMI ‘vastly underestimates’ true obesity
CHICAGO – , a finding that highlights the shortcomings of BMI and adds to the growing case that BMI alone should not be the default gauge for obesity.
“BMI vastly underestimates true obesity,” Aayush Visaria, MD, said at the annual meeting of the Endocrine Society.
His findings highlight that “BMI should be supplemented with other measures of obesity” for the management of individual patients, with assessments that could include a bioelectrical impedance scale or waist circumference, said Dr. Visaria, a researcher at Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J.
Dr. Visaria cited a new policy issued by the American Medical Association a couple of days before his presentation, which advises that BMI “be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.”
“We’re at the start of the end of BMI,” Dr. Visaria declared during a press briefing at the meeting.
He said DEXA is not practical or cost-effective for obesity screening in routine practice. Therefore, he predicts that waist circumference, often expressed as waist-to-height ratio, will be measured more often, although he acknowledged that waist measurement can be difficult. However, better physician training on the measure should help it become the norm.
Another useful tool for obesity measurement he foresees quickly becoming widespread is bathroom scales that record both weight and body fat percentage using a small electric current to make a bioelectrical impedance measure of adiposity.
Bioimpedance scales will provide more standardized measurements than waist circumference and “revolutionize how we measure obesity,” Dr. Visaria predicted. They are “very accessible and cheap,” he noted, with many models sold for less than $100.
Obesity prevalence of 74%
The study by Dr. Visaria and colleagues used data from 9,784 U.S. adults aged 20-59 years (average age, 39 years) collected in several National Health and Nutrition Examination Surveys during 2011-2018. All these participants underwent DEXA assessment of their total body fat as well as a BMI calculation.
Using standard obesity cutoffs for both BMI and total body fat, Dr. Visaria found that DEXA rated 74% of participants as having obesity based on body fat compared with 36% based on BMI.
Among the 64% of the study group who were not obese by BMI, DEXA scans showed 53% of this subgroup did have obesity based on body fat content. Among those with a normal BMI, 43% had obesity by DEXA result.
Further analysis showed that when Dr. Visaria added waist circumference to BMI to enlarge the diagnostic net for obesity it cut the percentage of adults missed as having obesity by BMI alone nearly in half.
Additional analyses showed that the rate of missed diagnoses of obesity by BMI was most common only among people of Hispanic or Asian ethnicity, with both groups showing a 49% rate of obesity by DEXA among those with normal-range BMIs.
The rate of missed obesity diagnoses was highest among all women, with a 59% prevalence of obesity by DEXA among women with a normal-range BMI.
The study received no commercial funding. Dr. Visaria has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – , a finding that highlights the shortcomings of BMI and adds to the growing case that BMI alone should not be the default gauge for obesity.
“BMI vastly underestimates true obesity,” Aayush Visaria, MD, said at the annual meeting of the Endocrine Society.
His findings highlight that “BMI should be supplemented with other measures of obesity” for the management of individual patients, with assessments that could include a bioelectrical impedance scale or waist circumference, said Dr. Visaria, a researcher at Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J.
Dr. Visaria cited a new policy issued by the American Medical Association a couple of days before his presentation, which advises that BMI “be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.”
“We’re at the start of the end of BMI,” Dr. Visaria declared during a press briefing at the meeting.
He said DEXA is not practical or cost-effective for obesity screening in routine practice. Therefore, he predicts that waist circumference, often expressed as waist-to-height ratio, will be measured more often, although he acknowledged that waist measurement can be difficult. However, better physician training on the measure should help it become the norm.
Another useful tool for obesity measurement he foresees quickly becoming widespread is bathroom scales that record both weight and body fat percentage using a small electric current to make a bioelectrical impedance measure of adiposity.
Bioimpedance scales will provide more standardized measurements than waist circumference and “revolutionize how we measure obesity,” Dr. Visaria predicted. They are “very accessible and cheap,” he noted, with many models sold for less than $100.
Obesity prevalence of 74%
The study by Dr. Visaria and colleagues used data from 9,784 U.S. adults aged 20-59 years (average age, 39 years) collected in several National Health and Nutrition Examination Surveys during 2011-2018. All these participants underwent DEXA assessment of their total body fat as well as a BMI calculation.
Using standard obesity cutoffs for both BMI and total body fat, Dr. Visaria found that DEXA rated 74% of participants as having obesity based on body fat compared with 36% based on BMI.
Among the 64% of the study group who were not obese by BMI, DEXA scans showed 53% of this subgroup did have obesity based on body fat content. Among those with a normal BMI, 43% had obesity by DEXA result.
Further analysis showed that when Dr. Visaria added waist circumference to BMI to enlarge the diagnostic net for obesity it cut the percentage of adults missed as having obesity by BMI alone nearly in half.
Additional analyses showed that the rate of missed diagnoses of obesity by BMI was most common only among people of Hispanic or Asian ethnicity, with both groups showing a 49% rate of obesity by DEXA among those with normal-range BMIs.
The rate of missed obesity diagnoses was highest among all women, with a 59% prevalence of obesity by DEXA among women with a normal-range BMI.
The study received no commercial funding. Dr. Visaria has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – , a finding that highlights the shortcomings of BMI and adds to the growing case that BMI alone should not be the default gauge for obesity.
“BMI vastly underestimates true obesity,” Aayush Visaria, MD, said at the annual meeting of the Endocrine Society.
His findings highlight that “BMI should be supplemented with other measures of obesity” for the management of individual patients, with assessments that could include a bioelectrical impedance scale or waist circumference, said Dr. Visaria, a researcher at Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J.
Dr. Visaria cited a new policy issued by the American Medical Association a couple of days before his presentation, which advises that BMI “be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.”
“We’re at the start of the end of BMI,” Dr. Visaria declared during a press briefing at the meeting.
He said DEXA is not practical or cost-effective for obesity screening in routine practice. Therefore, he predicts that waist circumference, often expressed as waist-to-height ratio, will be measured more often, although he acknowledged that waist measurement can be difficult. However, better physician training on the measure should help it become the norm.
Another useful tool for obesity measurement he foresees quickly becoming widespread is bathroom scales that record both weight and body fat percentage using a small electric current to make a bioelectrical impedance measure of adiposity.
Bioimpedance scales will provide more standardized measurements than waist circumference and “revolutionize how we measure obesity,” Dr. Visaria predicted. They are “very accessible and cheap,” he noted, with many models sold for less than $100.
Obesity prevalence of 74%
The study by Dr. Visaria and colleagues used data from 9,784 U.S. adults aged 20-59 years (average age, 39 years) collected in several National Health and Nutrition Examination Surveys during 2011-2018. All these participants underwent DEXA assessment of their total body fat as well as a BMI calculation.
Using standard obesity cutoffs for both BMI and total body fat, Dr. Visaria found that DEXA rated 74% of participants as having obesity based on body fat compared with 36% based on BMI.
Among the 64% of the study group who were not obese by BMI, DEXA scans showed 53% of this subgroup did have obesity based on body fat content. Among those with a normal BMI, 43% had obesity by DEXA result.
Further analysis showed that when Dr. Visaria added waist circumference to BMI to enlarge the diagnostic net for obesity it cut the percentage of adults missed as having obesity by BMI alone nearly in half.
Additional analyses showed that the rate of missed diagnoses of obesity by BMI was most common only among people of Hispanic or Asian ethnicity, with both groups showing a 49% rate of obesity by DEXA among those with normal-range BMIs.
The rate of missed obesity diagnoses was highest among all women, with a 59% prevalence of obesity by DEXA among women with a normal-range BMI.
The study received no commercial funding. Dr. Visaria has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ENDO 2023
Anabolic-steroid withdrawal regimens show promise in men
Men who illicitly used anabolic-androgenic steroids to bulk up and then turned to illegal, web-based regimens for treating their steroid withdrawal complications have provided important clues for new approaches to treating a growing worldwide population of men who abuse steroids.
A retrospective, observational study at one steroid addiction center in Glasgow examined 641 men who had stopped using steroids within the prior 3 years in 2015-2022 and who had self-administered certain agents, collectively known as post-cycle therapy (PCT) – within 3 months of stopping steroids.
They had a significant 3.8-fold increased rate of normalization of their levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), compared with men who either never used PCT or began it more than 3 months after stopping steroids, Channa N. Jayasena, PhD, MRCP, FRCPath, reported at the annual meeting of the Endocrine Society.
These testosterone, LH, and FSH levels served as a “surrogate marker of biochemical recovery from hypogonadism,” he explained. Normalization also occurred “slightly sooner” in men who began using PCT early after steroid cessation, added Dr. Jayasena, a reproductive endocrinologist at Imperial College, London.
When men recovered their endogenous testosterone-producing capacity, it occurred after an average of about 13 weeks on PCT and after an average of about 19 weeks without PCT, a significant difference.
“There is a vacuum of medical advice on what to do” when men stop taking steroids, said Dr. Jayasena during a press briefing at the meeting. “We can’t recommend anything yet because [our studies] have not proven causality” between the post-cycle therapy that many men start after stopping steroids and any symptom improvement they experience.”
The next step is to test the PCT agents in a prospective, controlled study, an investigation Dr. Jayasena and colleagues are eager to launch. The goal is to determine whether PCT is truly effective, the optimal doses, and whether the treatments are safe.
‘Incredibly sophisticated’ online community
The agents that constitute PCT include human chorionic gonadotropin (hCG, the “pregnancy hormone”), selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs). SERMs and AIs are licensed only for use in women, the former for osteoporosis and breast cancer and the latter for breast cancer.
All of these agents, as well as others, are advertised by various illegal websites as treatments that can restore endogenous testosterone production in men whose native testosterone shut down during their steroid self-medication.
Restored testosterone resolves many of the adverse effects of steroid withdrawal such as diminished libido and erections, and depressed mood and energy.
Men buy PCT agents illegally from various websites. “There is an enormous, incredibly sophisticated community online that influences” PCT, and an “incredibly refined worldwide distribution network,” Dr. Jayasena explained.
His study included 410 men who turned to PCT after steroid cessation and 170 who did not.
Largest study of hormone recovery when men stop taking steroids
In a further multivariate analysis of the observational data, men who had used four or more different steroid treatments fared worse – with a significant 75% reduced rate of testosterone normalization with PCT – compared with men who had used a single steroid agent.
And men who had been on a steroid regimen for more than 6 months also fared badly – with a significant 66% reduced rate of testosterone normalization with PCT, compared with men on a steroid regimen for 3 months or less.
“This is the largest study of hormone recovery when men stop taking steroids,” Dr. Jayasena noted.
And the data “require corroboration within an interventional study to determine causality.”
“We need further studies to help doctors and other health care professionals advise men about the risks of anabolic steroid use and support those who are motivated to stop,” Dr. Jayasena said.
He cautioned that the study has several limitations: biases were potentially introduced based on recruitment and on recall by participants; clinicians drew blood specimens used to measure hormone levels at random times; and participants may have engaged in concealed drug use and used steroid and PCT agents that did not contain the substances advertised.
Nevertheless,, and they “may have important therapeutic implications for the future treatment of men who are motivated to stop” steroids.
The study received no commercial funding. Dr. Jayasena has received research funding from Logixx Pharma.
A version of this article first appeared on Medscape.com.
Men who illicitly used anabolic-androgenic steroids to bulk up and then turned to illegal, web-based regimens for treating their steroid withdrawal complications have provided important clues for new approaches to treating a growing worldwide population of men who abuse steroids.
A retrospective, observational study at one steroid addiction center in Glasgow examined 641 men who had stopped using steroids within the prior 3 years in 2015-2022 and who had self-administered certain agents, collectively known as post-cycle therapy (PCT) – within 3 months of stopping steroids.
They had a significant 3.8-fold increased rate of normalization of their levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), compared with men who either never used PCT or began it more than 3 months after stopping steroids, Channa N. Jayasena, PhD, MRCP, FRCPath, reported at the annual meeting of the Endocrine Society.
These testosterone, LH, and FSH levels served as a “surrogate marker of biochemical recovery from hypogonadism,” he explained. Normalization also occurred “slightly sooner” in men who began using PCT early after steroid cessation, added Dr. Jayasena, a reproductive endocrinologist at Imperial College, London.
When men recovered their endogenous testosterone-producing capacity, it occurred after an average of about 13 weeks on PCT and after an average of about 19 weeks without PCT, a significant difference.
“There is a vacuum of medical advice on what to do” when men stop taking steroids, said Dr. Jayasena during a press briefing at the meeting. “We can’t recommend anything yet because [our studies] have not proven causality” between the post-cycle therapy that many men start after stopping steroids and any symptom improvement they experience.”
The next step is to test the PCT agents in a prospective, controlled study, an investigation Dr. Jayasena and colleagues are eager to launch. The goal is to determine whether PCT is truly effective, the optimal doses, and whether the treatments are safe.
‘Incredibly sophisticated’ online community
The agents that constitute PCT include human chorionic gonadotropin (hCG, the “pregnancy hormone”), selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs). SERMs and AIs are licensed only for use in women, the former for osteoporosis and breast cancer and the latter for breast cancer.
All of these agents, as well as others, are advertised by various illegal websites as treatments that can restore endogenous testosterone production in men whose native testosterone shut down during their steroid self-medication.
Restored testosterone resolves many of the adverse effects of steroid withdrawal such as diminished libido and erections, and depressed mood and energy.
Men buy PCT agents illegally from various websites. “There is an enormous, incredibly sophisticated community online that influences” PCT, and an “incredibly refined worldwide distribution network,” Dr. Jayasena explained.
His study included 410 men who turned to PCT after steroid cessation and 170 who did not.
Largest study of hormone recovery when men stop taking steroids
In a further multivariate analysis of the observational data, men who had used four or more different steroid treatments fared worse – with a significant 75% reduced rate of testosterone normalization with PCT – compared with men who had used a single steroid agent.
And men who had been on a steroid regimen for more than 6 months also fared badly – with a significant 66% reduced rate of testosterone normalization with PCT, compared with men on a steroid regimen for 3 months or less.
“This is the largest study of hormone recovery when men stop taking steroids,” Dr. Jayasena noted.
And the data “require corroboration within an interventional study to determine causality.”
“We need further studies to help doctors and other health care professionals advise men about the risks of anabolic steroid use and support those who are motivated to stop,” Dr. Jayasena said.
He cautioned that the study has several limitations: biases were potentially introduced based on recruitment and on recall by participants; clinicians drew blood specimens used to measure hormone levels at random times; and participants may have engaged in concealed drug use and used steroid and PCT agents that did not contain the substances advertised.
Nevertheless,, and they “may have important therapeutic implications for the future treatment of men who are motivated to stop” steroids.
The study received no commercial funding. Dr. Jayasena has received research funding from Logixx Pharma.
A version of this article first appeared on Medscape.com.
Men who illicitly used anabolic-androgenic steroids to bulk up and then turned to illegal, web-based regimens for treating their steroid withdrawal complications have provided important clues for new approaches to treating a growing worldwide population of men who abuse steroids.
A retrospective, observational study at one steroid addiction center in Glasgow examined 641 men who had stopped using steroids within the prior 3 years in 2015-2022 and who had self-administered certain agents, collectively known as post-cycle therapy (PCT) – within 3 months of stopping steroids.
They had a significant 3.8-fold increased rate of normalization of their levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), compared with men who either never used PCT or began it more than 3 months after stopping steroids, Channa N. Jayasena, PhD, MRCP, FRCPath, reported at the annual meeting of the Endocrine Society.
These testosterone, LH, and FSH levels served as a “surrogate marker of biochemical recovery from hypogonadism,” he explained. Normalization also occurred “slightly sooner” in men who began using PCT early after steroid cessation, added Dr. Jayasena, a reproductive endocrinologist at Imperial College, London.
When men recovered their endogenous testosterone-producing capacity, it occurred after an average of about 13 weeks on PCT and after an average of about 19 weeks without PCT, a significant difference.
“There is a vacuum of medical advice on what to do” when men stop taking steroids, said Dr. Jayasena during a press briefing at the meeting. “We can’t recommend anything yet because [our studies] have not proven causality” between the post-cycle therapy that many men start after stopping steroids and any symptom improvement they experience.”
The next step is to test the PCT agents in a prospective, controlled study, an investigation Dr. Jayasena and colleagues are eager to launch. The goal is to determine whether PCT is truly effective, the optimal doses, and whether the treatments are safe.
‘Incredibly sophisticated’ online community
The agents that constitute PCT include human chorionic gonadotropin (hCG, the “pregnancy hormone”), selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs). SERMs and AIs are licensed only for use in women, the former for osteoporosis and breast cancer and the latter for breast cancer.
All of these agents, as well as others, are advertised by various illegal websites as treatments that can restore endogenous testosterone production in men whose native testosterone shut down during their steroid self-medication.
Restored testosterone resolves many of the adverse effects of steroid withdrawal such as diminished libido and erections, and depressed mood and energy.
Men buy PCT agents illegally from various websites. “There is an enormous, incredibly sophisticated community online that influences” PCT, and an “incredibly refined worldwide distribution network,” Dr. Jayasena explained.
His study included 410 men who turned to PCT after steroid cessation and 170 who did not.
Largest study of hormone recovery when men stop taking steroids
In a further multivariate analysis of the observational data, men who had used four or more different steroid treatments fared worse – with a significant 75% reduced rate of testosterone normalization with PCT – compared with men who had used a single steroid agent.
And men who had been on a steroid regimen for more than 6 months also fared badly – with a significant 66% reduced rate of testosterone normalization with PCT, compared with men on a steroid regimen for 3 months or less.
“This is the largest study of hormone recovery when men stop taking steroids,” Dr. Jayasena noted.
And the data “require corroboration within an interventional study to determine causality.”
“We need further studies to help doctors and other health care professionals advise men about the risks of anabolic steroid use and support those who are motivated to stop,” Dr. Jayasena said.
He cautioned that the study has several limitations: biases were potentially introduced based on recruitment and on recall by participants; clinicians drew blood specimens used to measure hormone levels at random times; and participants may have engaged in concealed drug use and used steroid and PCT agents that did not contain the substances advertised.
Nevertheless,, and they “may have important therapeutic implications for the future treatment of men who are motivated to stop” steroids.
The study received no commercial funding. Dr. Jayasena has received research funding from Logixx Pharma.
A version of this article first appeared on Medscape.com.
FROM ENDO 2023
PCOS associated with shorter lifespan
CHICAGO –
In the study, involving nearly 10,000 women with PCOS and matched controls from Finland, women with PCOS died on average a year earlier than their age-matched counterparts, primarily from diseases of the circulatory system, cancer, and diabetes.
PCOS is the most common endocrine disorder of reproductive-age women, of whom about 50%-70% also have obesity.
“I think we need to acknowledge that this is a health burden and not just a reproductive problem. In many cases we deal with the reproductive problem, and then these women are left alone. … So I think the message is we need to look beyond the reproductive outcomes, which are … really good. We can manage that,” said Terhi T. Piltonen, MD, PhD, during a press briefing held June 15 at the annual meeting of the Endocrine Society.
“I think the difficult part is [managing] the lifelong health for these women and supporting them to achieve the best health they can get. We need a multidisciplinary effort and to put more resources into the research,” added Dr. Piltonen, professor in the departments of ob.gyn. and reproductive endocrinology at the University of Oulu, Finland.
Indeed, Punith Kempegowda, MD, PhD, of the University of Birmingham (England) observed: “In our medical schools in the U.K., over 5 years, students get 45 minutes [of education] on PCOS, and they’re expected to learn about it.”
And over the last 20 years, funding for research into the condition has totaled less than a half percent of overall medical funding. “And we’re talking about 10% of all women. …We need to acknowledge it and educate people more. We need more published studies to understand more about it,” he noted.
Asked to comment, Greg Dodell, MD, owner and president of Central Park Endocrinology, New York, said: “PCOS is about a lot more than fertility, and that may not be the goal or on the mind of a woman at the time they start having symptoms of PCOS or get the diagnosis.”
“PCOS is largely a metabolic condition rooted in insulin resistance, and therefore, the potential clinical outcomes, including mortality, are important to recognize.”
Dr. Dodell, who has a special interest in PCOS, advised that, for women with the condition, “focus on reducing insulin resistance with health-promoting behaviors and medications as needed. Data demonstrate that improving fitness, irrespective of a change in weight, can improve metabolic markers.” And, he advised that these women be routinely screened for mental health issues.
He also noted, “PCOS occurs across the size spectrum, but those patients in larger bodies may face weight stigma which has negative health consequences. These patients may avoid going to doctors for routine health screenings, so it is an important issue to continue to address.”
Women with PCOS lose a year of life
The new data come from 9,839 women with PCOS and 70,705 age- and region-matched controls from the Finnish Care Register for Health Care. The group with PCOS had been diagnosed at a mean age of 27 years.
The mean follow-up time was 13.1 years in both groups, during which 1,003 controls and 177 women with PCOS died. The mean age at death was 51.4 years for the PCOS group versus 52.6 years for the control women, a significant difference (P < .001).
Causes of death that were significantly higher among the women with PCOS versus controls after adjustments were cancer (hazard ratio, 1.39), and diseases of the circulatory system (1.68).
In more specific subcategories, after adjustment for education, the women with PCOS had increased mortality from nonischemic diseases, such as hypertensive heart disease, pulmonary embolism, etc. (HR, 2.06), and diabetes (HR, 2.85).
One study limitation was the inability to adjust for body mass index, Dr. Piltonen noted.
Dr. Piltonen, Dr. Kempegowda, and Dr. Dodell have no disclosures.
CHICAGO –
In the study, involving nearly 10,000 women with PCOS and matched controls from Finland, women with PCOS died on average a year earlier than their age-matched counterparts, primarily from diseases of the circulatory system, cancer, and diabetes.
PCOS is the most common endocrine disorder of reproductive-age women, of whom about 50%-70% also have obesity.
“I think we need to acknowledge that this is a health burden and not just a reproductive problem. In many cases we deal with the reproductive problem, and then these women are left alone. … So I think the message is we need to look beyond the reproductive outcomes, which are … really good. We can manage that,” said Terhi T. Piltonen, MD, PhD, during a press briefing held June 15 at the annual meeting of the Endocrine Society.
“I think the difficult part is [managing] the lifelong health for these women and supporting them to achieve the best health they can get. We need a multidisciplinary effort and to put more resources into the research,” added Dr. Piltonen, professor in the departments of ob.gyn. and reproductive endocrinology at the University of Oulu, Finland.
Indeed, Punith Kempegowda, MD, PhD, of the University of Birmingham (England) observed: “In our medical schools in the U.K., over 5 years, students get 45 minutes [of education] on PCOS, and they’re expected to learn about it.”
And over the last 20 years, funding for research into the condition has totaled less than a half percent of overall medical funding. “And we’re talking about 10% of all women. …We need to acknowledge it and educate people more. We need more published studies to understand more about it,” he noted.
Asked to comment, Greg Dodell, MD, owner and president of Central Park Endocrinology, New York, said: “PCOS is about a lot more than fertility, and that may not be the goal or on the mind of a woman at the time they start having symptoms of PCOS or get the diagnosis.”
“PCOS is largely a metabolic condition rooted in insulin resistance, and therefore, the potential clinical outcomes, including mortality, are important to recognize.”
Dr. Dodell, who has a special interest in PCOS, advised that, for women with the condition, “focus on reducing insulin resistance with health-promoting behaviors and medications as needed. Data demonstrate that improving fitness, irrespective of a change in weight, can improve metabolic markers.” And, he advised that these women be routinely screened for mental health issues.
He also noted, “PCOS occurs across the size spectrum, but those patients in larger bodies may face weight stigma which has negative health consequences. These patients may avoid going to doctors for routine health screenings, so it is an important issue to continue to address.”
Women with PCOS lose a year of life
The new data come from 9,839 women with PCOS and 70,705 age- and region-matched controls from the Finnish Care Register for Health Care. The group with PCOS had been diagnosed at a mean age of 27 years.
The mean follow-up time was 13.1 years in both groups, during which 1,003 controls and 177 women with PCOS died. The mean age at death was 51.4 years for the PCOS group versus 52.6 years for the control women, a significant difference (P < .001).
Causes of death that were significantly higher among the women with PCOS versus controls after adjustments were cancer (hazard ratio, 1.39), and diseases of the circulatory system (1.68).
In more specific subcategories, after adjustment for education, the women with PCOS had increased mortality from nonischemic diseases, such as hypertensive heart disease, pulmonary embolism, etc. (HR, 2.06), and diabetes (HR, 2.85).
One study limitation was the inability to adjust for body mass index, Dr. Piltonen noted.
Dr. Piltonen, Dr. Kempegowda, and Dr. Dodell have no disclosures.
CHICAGO –
In the study, involving nearly 10,000 women with PCOS and matched controls from Finland, women with PCOS died on average a year earlier than their age-matched counterparts, primarily from diseases of the circulatory system, cancer, and diabetes.
PCOS is the most common endocrine disorder of reproductive-age women, of whom about 50%-70% also have obesity.
“I think we need to acknowledge that this is a health burden and not just a reproductive problem. In many cases we deal with the reproductive problem, and then these women are left alone. … So I think the message is we need to look beyond the reproductive outcomes, which are … really good. We can manage that,” said Terhi T. Piltonen, MD, PhD, during a press briefing held June 15 at the annual meeting of the Endocrine Society.
“I think the difficult part is [managing] the lifelong health for these women and supporting them to achieve the best health they can get. We need a multidisciplinary effort and to put more resources into the research,” added Dr. Piltonen, professor in the departments of ob.gyn. and reproductive endocrinology at the University of Oulu, Finland.
Indeed, Punith Kempegowda, MD, PhD, of the University of Birmingham (England) observed: “In our medical schools in the U.K., over 5 years, students get 45 minutes [of education] on PCOS, and they’re expected to learn about it.”
And over the last 20 years, funding for research into the condition has totaled less than a half percent of overall medical funding. “And we’re talking about 10% of all women. …We need to acknowledge it and educate people more. We need more published studies to understand more about it,” he noted.
Asked to comment, Greg Dodell, MD, owner and president of Central Park Endocrinology, New York, said: “PCOS is about a lot more than fertility, and that may not be the goal or on the mind of a woman at the time they start having symptoms of PCOS or get the diagnosis.”
“PCOS is largely a metabolic condition rooted in insulin resistance, and therefore, the potential clinical outcomes, including mortality, are important to recognize.”
Dr. Dodell, who has a special interest in PCOS, advised that, for women with the condition, “focus on reducing insulin resistance with health-promoting behaviors and medications as needed. Data demonstrate that improving fitness, irrespective of a change in weight, can improve metabolic markers.” And, he advised that these women be routinely screened for mental health issues.
He also noted, “PCOS occurs across the size spectrum, but those patients in larger bodies may face weight stigma which has negative health consequences. These patients may avoid going to doctors for routine health screenings, so it is an important issue to continue to address.”
Women with PCOS lose a year of life
The new data come from 9,839 women with PCOS and 70,705 age- and region-matched controls from the Finnish Care Register for Health Care. The group with PCOS had been diagnosed at a mean age of 27 years.
The mean follow-up time was 13.1 years in both groups, during which 1,003 controls and 177 women with PCOS died. The mean age at death was 51.4 years for the PCOS group versus 52.6 years for the control women, a significant difference (P < .001).
Causes of death that were significantly higher among the women with PCOS versus controls after adjustments were cancer (hazard ratio, 1.39), and diseases of the circulatory system (1.68).
In more specific subcategories, after adjustment for education, the women with PCOS had increased mortality from nonischemic diseases, such as hypertensive heart disease, pulmonary embolism, etc. (HR, 2.06), and diabetes (HR, 2.85).
One study limitation was the inability to adjust for body mass index, Dr. Piltonen noted.
Dr. Piltonen, Dr. Kempegowda, and Dr. Dodell have no disclosures.
AT ENDO 2023
Big trial reassures on heart safety of testosterone in men
CHICAGO – , long-awaited results from a major clinical trial show.
Among over 5,000 men aged 45-80 years randomized to daily transdermal testosterone gel or matching placebo gel for an average of 22 months, no increased risk was seen for a first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
There was also no increased risk for prostate cancer over the 33-month follow-up period. However, there were increases in rates of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone group.
In terms of efficacy, testosterone therapy was associated with improved sexual function over two years of treatment and correction, or prevention, of anemia, but had no effect on progression to diabetes or glycemic parameters.
And, an unexpected finding was a significant and unexplained 43% increase in fractures with testosterone therapy.
The TRAVERSE study was mandated by the Food and Drug Administration in 2015 in response to concerns and conflicting data regarding the cardiovascular safety of testosterone replacement therapy in men. It was conducted by a consortium of five manufacturers of testosterone replacement products, led by AbbVie.
The results were presented during a symposium at the annual meeting of the Endocrine Society. The mandated safety data were published online in the New England Journal of Medicine. The efficacy outcomes, undertaken opportunistically due to the trial’s large sample size and relatively long followup time, will be published later this year.
Taken together, the TRAVERSE findings are expected to transform the risk–benefit discussions with patients about the use of testosterone therapy for hypogonadism, study coauthor Shalender Bhasin, MD, told this news organization.
“Testosterone deficiency doesn’t kill people as far as we know but it is really an important symptomatic condition that affects quality of life. Many middle-aged and older men seek assistance for these symptoms, so it’s an important condition and the treatment decisions are complicated,” said Dr. Bhasin, director of the research program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital in Boston.
These new data will be incorporated into future guidelines on testosterone therapy in men with hypoandrogenism, noted Dr. Bhasin, a coauthor of The Endocrine Society’s 2018 guidelines.
Findings apply only to men with bona fide testosterone deficiency
Asked to comment, endocrinologist Bradley D. Anawalt, MD, told this news organization that “the community of physicians who prescribe testosterone to men was waiting with bated breath” for the TRAVERSE results.
“Until now, we’ve had to say well, there might be a risk of strokes and heart attacks. This study does a lot to say that’s not a serious risk, in the first few years anyway, of testosterone therapy. We still need long-term follow-up in these patients, or others, to see what the long-term risks are, but it’s really reassuring,” added Dr. Anawalt, professor of medicine at the University of Washington, Seattle.
Both Dr. Bhasin and Dr. Anawalt said the TRAVERSE trial in men is similar in many ways to the Women’s Health Initiative (WHI). “[TRAVERSE] is not as big as [WHI], but it’s framed in a similar way to ask those safety questions and to weigh the risk and benefit,” Dr. Anawalt explained.
However, Dr. Anawalt stressed that the TRAVERSE safety data apply only to men with documented testosterone deficiency.
“It’s important to emphasize that this is a study of men with bona fide testosterone deficiency and symptoms. It doesn’t give carte blanche to prescribe to men with normal testosterone concentrations. It doesn’t tell us about the safety of that,” he noted.
Safety reassuring, but some concerns will require more investigation
TRAVERSE was a multicenter, randomized, double-blind, placebo-controlled noninferiority trial that enrolled 5246 men aged 45-80 years. Participants had pre-existing or were at high risk of cardiovascular disease, reported symptoms of hypogonadism, and had two fasting testosterone levels < 300 ng/dL. They were randomly assigned to receive daily transdermal 1.62% testosterone gel or placebo gel.
The primary safety endpoint event (first adjudicated major adverse cardiac event) occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; P < .001 for noninferiority). Similar results were seen in sensitivity analyses.
Pulmonary embolism occurred in 0.9% of the testosterone group versus 0.5% of the placebo group, supporting current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events, the authors note.
Prostate cancer occurred in 0.5% (n = 12) of patients in the testosterone group and 0.4% (n = 11) of patients in the placebo group, not a significant difference (P = .87).
There were, however, significant differences between the testosterone and placebo groups in terms of nonfatal arrhythmias warranting intervention (5.2% vs. 3.3%; P = .001), atrial fibrillation (3.5% vs. 2.4%; P = .02), and acute kidney injury (2.3% vs. 1.5%; P = .04).
“These adverse events were not expected,” the authors wrote.
Dr. Bhasin said that the team plans to investigate those cases further to look for possible risk factors, including whether COVID-19 played a role in these outcomes because the trial took place during the pandemic and some participants in both study groups contracted the virus.
Regarding acute kidney injury, Dr. Anawalt said: “I don’t know that I believe that ... It’s probably a statistical abnormality. It barely made ... significance.”
Finally, ‘real data on something we’ve been prescribing for decades’
Both Dr. Bhasin and Dr. Anawalt pointed out the deficiencies in the prior literature in terms of what has been known about testosterone’s effects. According to Dr. Bhasin, “In spite of all the folklore, there isn’t very much known about the efficacy of treatment beyond sexual function, and even there, the data are really limited. Most trials have been open-label and very small.”
He added that even among the few previous randomized clinical trials, only one, the TTrials series, had an adequate number of participants and used robust measures to assess sexual function, but that study only lasted a year.
Indeed, Dr. Anawalt noted, “[TRAVERSE] and its father study, the TTrials, were the first systematic studies to look at large groups of men getting testosterone versus placebo. We’re now starting to get real data on something that we’ve been prescribing for decades.”
At the ENDO symposium, Dr. Bhasin presented data showing significant improvements with testosterone compared to placebo in overall sexual activity (P = .011), sexual symptoms (P < .001), and sexual desire over one year, and maintained over two years in TRAVERSE. All were assessed by validated questionnaires.
“They confirmed that there’s an improvement in sexual function and that it’s sustained. That’s important because there had been doubt about that ... and it sounds like it’s clinically significant,” Dr. Anawalt said.
Testosterone therapy was also associated with lower rates of anemia among men who were not anemic at baseline, and lower incidence of anemia in those who were anemic to begin with. However, the rate of progression from prediabetes to diabetes didn’t differ significantly, nor did testosterone therapy improve glycemic control or remission in men who had diabetes at baseline, Dr. Bhasin reported.
‘Big surprise’ and a mystery: Testosterone increased fracture risk
The fracture data were presented by Peter J. Snyder, MD, of the University of Pennsylvania, who earlier in the session had received an Endocrine Society award for his work in the testosterone field.
“No prior trial of testosterone treatment of hypogonadal men has been large enough or long enough to assess its effect on fractures ... until the TRAVERSE trial,” he said.
The hypothesis going in was that testosterone would decrease the fracture incidence, since prior data had suggested it improves many parameters of bone quality in elderly men and in those with severe hypogonadism.
Instead, there were 91 confirmed and adjudicated clinical fractures in the testosterone group versus 64 in the placebo group, giving a hazard ratio of 1.43 (P = .03). The risk was seen across fracture types, increasing the likelihood that this finding was, in fact, real, Dr. Snyder said.
“We could speculate about a possible mechanism, but because we did not expect these results, we did not design the trial to evaluate a possible mechanism,” Dr. Snyder noted.
Dr. Anawalt told this news organization that the fracture finding “was a big surprise. None of us would have expected that there would be an increase in fractures.”
Clinically, Dr. Anawalt said it suggests consideration of expanding the use of anti-osteoporotic medication such as bisphosphonates to men with low testosterone and elevated fracture risk for whom clinicians may have assumed that just giving them testosterone replacement might also protect their bones.
“This begs the question should we reorient the way we’re thinking about these men.”
The study was funded by AbbVie, Acerus Pharmaceuticals Corporation/Aytu Biosciences, Allergan Sales, Endo Pharmaceuticals, and Upsher-Smith Laboratories. Dr. Bhasin has disclosed grants to his institution from Function Promoting Therapies and Metro International Biotech, and owns stock in XYone. Dr. Anawalt has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 6/19/23.
CHICAGO – , long-awaited results from a major clinical trial show.
Among over 5,000 men aged 45-80 years randomized to daily transdermal testosterone gel or matching placebo gel for an average of 22 months, no increased risk was seen for a first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
There was also no increased risk for prostate cancer over the 33-month follow-up period. However, there were increases in rates of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone group.
In terms of efficacy, testosterone therapy was associated with improved sexual function over two years of treatment and correction, or prevention, of anemia, but had no effect on progression to diabetes or glycemic parameters.
And, an unexpected finding was a significant and unexplained 43% increase in fractures with testosterone therapy.
The TRAVERSE study was mandated by the Food and Drug Administration in 2015 in response to concerns and conflicting data regarding the cardiovascular safety of testosterone replacement therapy in men. It was conducted by a consortium of five manufacturers of testosterone replacement products, led by AbbVie.
The results were presented during a symposium at the annual meeting of the Endocrine Society. The mandated safety data were published online in the New England Journal of Medicine. The efficacy outcomes, undertaken opportunistically due to the trial’s large sample size and relatively long followup time, will be published later this year.
Taken together, the TRAVERSE findings are expected to transform the risk–benefit discussions with patients about the use of testosterone therapy for hypogonadism, study coauthor Shalender Bhasin, MD, told this news organization.
“Testosterone deficiency doesn’t kill people as far as we know but it is really an important symptomatic condition that affects quality of life. Many middle-aged and older men seek assistance for these symptoms, so it’s an important condition and the treatment decisions are complicated,” said Dr. Bhasin, director of the research program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital in Boston.
These new data will be incorporated into future guidelines on testosterone therapy in men with hypoandrogenism, noted Dr. Bhasin, a coauthor of The Endocrine Society’s 2018 guidelines.
Findings apply only to men with bona fide testosterone deficiency
Asked to comment, endocrinologist Bradley D. Anawalt, MD, told this news organization that “the community of physicians who prescribe testosterone to men was waiting with bated breath” for the TRAVERSE results.
“Until now, we’ve had to say well, there might be a risk of strokes and heart attacks. This study does a lot to say that’s not a serious risk, in the first few years anyway, of testosterone therapy. We still need long-term follow-up in these patients, or others, to see what the long-term risks are, but it’s really reassuring,” added Dr. Anawalt, professor of medicine at the University of Washington, Seattle.
Both Dr. Bhasin and Dr. Anawalt said the TRAVERSE trial in men is similar in many ways to the Women’s Health Initiative (WHI). “[TRAVERSE] is not as big as [WHI], but it’s framed in a similar way to ask those safety questions and to weigh the risk and benefit,” Dr. Anawalt explained.
However, Dr. Anawalt stressed that the TRAVERSE safety data apply only to men with documented testosterone deficiency.
“It’s important to emphasize that this is a study of men with bona fide testosterone deficiency and symptoms. It doesn’t give carte blanche to prescribe to men with normal testosterone concentrations. It doesn’t tell us about the safety of that,” he noted.
Safety reassuring, but some concerns will require more investigation
TRAVERSE was a multicenter, randomized, double-blind, placebo-controlled noninferiority trial that enrolled 5246 men aged 45-80 years. Participants had pre-existing or were at high risk of cardiovascular disease, reported symptoms of hypogonadism, and had two fasting testosterone levels < 300 ng/dL. They were randomly assigned to receive daily transdermal 1.62% testosterone gel or placebo gel.
The primary safety endpoint event (first adjudicated major adverse cardiac event) occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; P < .001 for noninferiority). Similar results were seen in sensitivity analyses.
Pulmonary embolism occurred in 0.9% of the testosterone group versus 0.5% of the placebo group, supporting current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events, the authors note.
Prostate cancer occurred in 0.5% (n = 12) of patients in the testosterone group and 0.4% (n = 11) of patients in the placebo group, not a significant difference (P = .87).
There were, however, significant differences between the testosterone and placebo groups in terms of nonfatal arrhythmias warranting intervention (5.2% vs. 3.3%; P = .001), atrial fibrillation (3.5% vs. 2.4%; P = .02), and acute kidney injury (2.3% vs. 1.5%; P = .04).
“These adverse events were not expected,” the authors wrote.
Dr. Bhasin said that the team plans to investigate those cases further to look for possible risk factors, including whether COVID-19 played a role in these outcomes because the trial took place during the pandemic and some participants in both study groups contracted the virus.
Regarding acute kidney injury, Dr. Anawalt said: “I don’t know that I believe that ... It’s probably a statistical abnormality. It barely made ... significance.”
Finally, ‘real data on something we’ve been prescribing for decades’
Both Dr. Bhasin and Dr. Anawalt pointed out the deficiencies in the prior literature in terms of what has been known about testosterone’s effects. According to Dr. Bhasin, “In spite of all the folklore, there isn’t very much known about the efficacy of treatment beyond sexual function, and even there, the data are really limited. Most trials have been open-label and very small.”
He added that even among the few previous randomized clinical trials, only one, the TTrials series, had an adequate number of participants and used robust measures to assess sexual function, but that study only lasted a year.
Indeed, Dr. Anawalt noted, “[TRAVERSE] and its father study, the TTrials, were the first systematic studies to look at large groups of men getting testosterone versus placebo. We’re now starting to get real data on something that we’ve been prescribing for decades.”
At the ENDO symposium, Dr. Bhasin presented data showing significant improvements with testosterone compared to placebo in overall sexual activity (P = .011), sexual symptoms (P < .001), and sexual desire over one year, and maintained over two years in TRAVERSE. All were assessed by validated questionnaires.
“They confirmed that there’s an improvement in sexual function and that it’s sustained. That’s important because there had been doubt about that ... and it sounds like it’s clinically significant,” Dr. Anawalt said.
Testosterone therapy was also associated with lower rates of anemia among men who were not anemic at baseline, and lower incidence of anemia in those who were anemic to begin with. However, the rate of progression from prediabetes to diabetes didn’t differ significantly, nor did testosterone therapy improve glycemic control or remission in men who had diabetes at baseline, Dr. Bhasin reported.
‘Big surprise’ and a mystery: Testosterone increased fracture risk
The fracture data were presented by Peter J. Snyder, MD, of the University of Pennsylvania, who earlier in the session had received an Endocrine Society award for his work in the testosterone field.
“No prior trial of testosterone treatment of hypogonadal men has been large enough or long enough to assess its effect on fractures ... until the TRAVERSE trial,” he said.
The hypothesis going in was that testosterone would decrease the fracture incidence, since prior data had suggested it improves many parameters of bone quality in elderly men and in those with severe hypogonadism.
Instead, there were 91 confirmed and adjudicated clinical fractures in the testosterone group versus 64 in the placebo group, giving a hazard ratio of 1.43 (P = .03). The risk was seen across fracture types, increasing the likelihood that this finding was, in fact, real, Dr. Snyder said.
“We could speculate about a possible mechanism, but because we did not expect these results, we did not design the trial to evaluate a possible mechanism,” Dr. Snyder noted.
Dr. Anawalt told this news organization that the fracture finding “was a big surprise. None of us would have expected that there would be an increase in fractures.”
Clinically, Dr. Anawalt said it suggests consideration of expanding the use of anti-osteoporotic medication such as bisphosphonates to men with low testosterone and elevated fracture risk for whom clinicians may have assumed that just giving them testosterone replacement might also protect their bones.
“This begs the question should we reorient the way we’re thinking about these men.”
The study was funded by AbbVie, Acerus Pharmaceuticals Corporation/Aytu Biosciences, Allergan Sales, Endo Pharmaceuticals, and Upsher-Smith Laboratories. Dr. Bhasin has disclosed grants to his institution from Function Promoting Therapies and Metro International Biotech, and owns stock in XYone. Dr. Anawalt has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 6/19/23.
CHICAGO – , long-awaited results from a major clinical trial show.
Among over 5,000 men aged 45-80 years randomized to daily transdermal testosterone gel or matching placebo gel for an average of 22 months, no increased risk was seen for a first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
There was also no increased risk for prostate cancer over the 33-month follow-up period. However, there were increases in rates of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone group.
In terms of efficacy, testosterone therapy was associated with improved sexual function over two years of treatment and correction, or prevention, of anemia, but had no effect on progression to diabetes or glycemic parameters.
And, an unexpected finding was a significant and unexplained 43% increase in fractures with testosterone therapy.
The TRAVERSE study was mandated by the Food and Drug Administration in 2015 in response to concerns and conflicting data regarding the cardiovascular safety of testosterone replacement therapy in men. It was conducted by a consortium of five manufacturers of testosterone replacement products, led by AbbVie.
The results were presented during a symposium at the annual meeting of the Endocrine Society. The mandated safety data were published online in the New England Journal of Medicine. The efficacy outcomes, undertaken opportunistically due to the trial’s large sample size and relatively long followup time, will be published later this year.
Taken together, the TRAVERSE findings are expected to transform the risk–benefit discussions with patients about the use of testosterone therapy for hypogonadism, study coauthor Shalender Bhasin, MD, told this news organization.
“Testosterone deficiency doesn’t kill people as far as we know but it is really an important symptomatic condition that affects quality of life. Many middle-aged and older men seek assistance for these symptoms, so it’s an important condition and the treatment decisions are complicated,” said Dr. Bhasin, director of the research program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital in Boston.
These new data will be incorporated into future guidelines on testosterone therapy in men with hypoandrogenism, noted Dr. Bhasin, a coauthor of The Endocrine Society’s 2018 guidelines.
Findings apply only to men with bona fide testosterone deficiency
Asked to comment, endocrinologist Bradley D. Anawalt, MD, told this news organization that “the community of physicians who prescribe testosterone to men was waiting with bated breath” for the TRAVERSE results.
“Until now, we’ve had to say well, there might be a risk of strokes and heart attacks. This study does a lot to say that’s not a serious risk, in the first few years anyway, of testosterone therapy. We still need long-term follow-up in these patients, or others, to see what the long-term risks are, but it’s really reassuring,” added Dr. Anawalt, professor of medicine at the University of Washington, Seattle.
Both Dr. Bhasin and Dr. Anawalt said the TRAVERSE trial in men is similar in many ways to the Women’s Health Initiative (WHI). “[TRAVERSE] is not as big as [WHI], but it’s framed in a similar way to ask those safety questions and to weigh the risk and benefit,” Dr. Anawalt explained.
However, Dr. Anawalt stressed that the TRAVERSE safety data apply only to men with documented testosterone deficiency.
“It’s important to emphasize that this is a study of men with bona fide testosterone deficiency and symptoms. It doesn’t give carte blanche to prescribe to men with normal testosterone concentrations. It doesn’t tell us about the safety of that,” he noted.
Safety reassuring, but some concerns will require more investigation
TRAVERSE was a multicenter, randomized, double-blind, placebo-controlled noninferiority trial that enrolled 5246 men aged 45-80 years. Participants had pre-existing or were at high risk of cardiovascular disease, reported symptoms of hypogonadism, and had two fasting testosterone levels < 300 ng/dL. They were randomly assigned to receive daily transdermal 1.62% testosterone gel or placebo gel.
The primary safety endpoint event (first adjudicated major adverse cardiac event) occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; P < .001 for noninferiority). Similar results were seen in sensitivity analyses.
Pulmonary embolism occurred in 0.9% of the testosterone group versus 0.5% of the placebo group, supporting current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events, the authors note.
Prostate cancer occurred in 0.5% (n = 12) of patients in the testosterone group and 0.4% (n = 11) of patients in the placebo group, not a significant difference (P = .87).
There were, however, significant differences between the testosterone and placebo groups in terms of nonfatal arrhythmias warranting intervention (5.2% vs. 3.3%; P = .001), atrial fibrillation (3.5% vs. 2.4%; P = .02), and acute kidney injury (2.3% vs. 1.5%; P = .04).
“These adverse events were not expected,” the authors wrote.
Dr. Bhasin said that the team plans to investigate those cases further to look for possible risk factors, including whether COVID-19 played a role in these outcomes because the trial took place during the pandemic and some participants in both study groups contracted the virus.
Regarding acute kidney injury, Dr. Anawalt said: “I don’t know that I believe that ... It’s probably a statistical abnormality. It barely made ... significance.”
Finally, ‘real data on something we’ve been prescribing for decades’
Both Dr. Bhasin and Dr. Anawalt pointed out the deficiencies in the prior literature in terms of what has been known about testosterone’s effects. According to Dr. Bhasin, “In spite of all the folklore, there isn’t very much known about the efficacy of treatment beyond sexual function, and even there, the data are really limited. Most trials have been open-label and very small.”
He added that even among the few previous randomized clinical trials, only one, the TTrials series, had an adequate number of participants and used robust measures to assess sexual function, but that study only lasted a year.
Indeed, Dr. Anawalt noted, “[TRAVERSE] and its father study, the TTrials, were the first systematic studies to look at large groups of men getting testosterone versus placebo. We’re now starting to get real data on something that we’ve been prescribing for decades.”
At the ENDO symposium, Dr. Bhasin presented data showing significant improvements with testosterone compared to placebo in overall sexual activity (P = .011), sexual symptoms (P < .001), and sexual desire over one year, and maintained over two years in TRAVERSE. All were assessed by validated questionnaires.
“They confirmed that there’s an improvement in sexual function and that it’s sustained. That’s important because there had been doubt about that ... and it sounds like it’s clinically significant,” Dr. Anawalt said.
Testosterone therapy was also associated with lower rates of anemia among men who were not anemic at baseline, and lower incidence of anemia in those who were anemic to begin with. However, the rate of progression from prediabetes to diabetes didn’t differ significantly, nor did testosterone therapy improve glycemic control or remission in men who had diabetes at baseline, Dr. Bhasin reported.
‘Big surprise’ and a mystery: Testosterone increased fracture risk
The fracture data were presented by Peter J. Snyder, MD, of the University of Pennsylvania, who earlier in the session had received an Endocrine Society award for his work in the testosterone field.
“No prior trial of testosterone treatment of hypogonadal men has been large enough or long enough to assess its effect on fractures ... until the TRAVERSE trial,” he said.
The hypothesis going in was that testosterone would decrease the fracture incidence, since prior data had suggested it improves many parameters of bone quality in elderly men and in those with severe hypogonadism.
Instead, there were 91 confirmed and adjudicated clinical fractures in the testosterone group versus 64 in the placebo group, giving a hazard ratio of 1.43 (P = .03). The risk was seen across fracture types, increasing the likelihood that this finding was, in fact, real, Dr. Snyder said.
“We could speculate about a possible mechanism, but because we did not expect these results, we did not design the trial to evaluate a possible mechanism,” Dr. Snyder noted.
Dr. Anawalt told this news organization that the fracture finding “was a big surprise. None of us would have expected that there would be an increase in fractures.”
Clinically, Dr. Anawalt said it suggests consideration of expanding the use of anti-osteoporotic medication such as bisphosphonates to men with low testosterone and elevated fracture risk for whom clinicians may have assumed that just giving them testosterone replacement might also protect their bones.
“This begs the question should we reorient the way we’re thinking about these men.”
The study was funded by AbbVie, Acerus Pharmaceuticals Corporation/Aytu Biosciences, Allergan Sales, Endo Pharmaceuticals, and Upsher-Smith Laboratories. Dr. Bhasin has disclosed grants to his institution from Function Promoting Therapies and Metro International Biotech, and owns stock in XYone. Dr. Anawalt has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 6/19/23.
AT ENDO 2023
Depression drives metabolic syndrome
Previous research has established a connection between metabolic syndrome and depression, but data on the increased risk for depressed individuals to develop metabolic syndrome (MetS) are lacking, wrote Lara Onofre Ferriani, PhD, of Federal University of Espírito Santo, Vitoria, Brazil, and colleagues.
“Individuals with MetS and depression have increased levels of inflammatory markers, and it is speculated that inflammation could mediate this comorbidity,” they said.
In a study published in the Journal of Psychiatric Research, the investigators reviewed data from 13,883 participants in the Brazilian Longitudinal Study of Adult Health; all were civil servants at universities in Brazil. The participants ranged from 35 to 74 years of age, with a mean age of 51.9 years; 54.3% were women; and 52.4% were white; the mean follow-up period was 3.8 years.
The primary outcome was the association between depression diagnosis and severity on components of MetS at baseline and over a 4-year period. Participants were classified by MetS trajectory as recovered, incident, or persistent, and classified by depression status as without depression or with a mild, moderate, or severe current depressive episode. Depression status was based on the Clinical Interview Schedule Revised. MetS components and diagnosis were based on the National Cholesterol Education Program Adult Treatment Panel III.
In a logistic regression analysis, baseline depression was positively associated with recovered, incident, and persistent MetS (odds ratios, 1.59, 1.45, and 1.70, respectively).
Depression at baseline also was significantly associated with separate components of MetS: large waist circumference, high triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia, with odds ratios of 1.47, 1.23, 1.30, and 1.38, respectively.
Although not seen at baseline, a significant positive association between baseline depression and the presence of three or more MetS components was noted at follow-up, with a positive dose-response effect, the researchers wrote in their discussion.
Not all associations were statistically significant, but this was mainly because of the small number of cases of moderate and severe depression, they said. However, the magnitude of associations was greater in severe depression, when compared with moderate and mild, which suggests that the risk of MetS may be higher in this population, they added.
The study findings were limited by several factors including the possible misclassification of depression, inability to differentiate among depressive subtypes, and the potential lack of generalizability to other populations beyond Brazilian civil servants, the researchers noted.
However, the results were strengthened by the large sample size and support the role of depression as a risk factor for MetS, they said. More research is needed to determine a bidirectional relationship and to assess the trajectory of depression after MetS develops, but the findings “highlight the need to investigate and manage metabolic and cardiovascular alterations in the presence of depression in clinical settings,” they concluded.
The study was supported by the Brazilian Ministry of Health (Science and Technology Department) and the Brazilian Ministry of Science, Technology and Innovation FINEP and CNPq, and by the Coordenaçaõ de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES). The researchers had no financial conflicts to disclose.
Previous research has established a connection between metabolic syndrome and depression, but data on the increased risk for depressed individuals to develop metabolic syndrome (MetS) are lacking, wrote Lara Onofre Ferriani, PhD, of Federal University of Espírito Santo, Vitoria, Brazil, and colleagues.
“Individuals with MetS and depression have increased levels of inflammatory markers, and it is speculated that inflammation could mediate this comorbidity,” they said.
In a study published in the Journal of Psychiatric Research, the investigators reviewed data from 13,883 participants in the Brazilian Longitudinal Study of Adult Health; all were civil servants at universities in Brazil. The participants ranged from 35 to 74 years of age, with a mean age of 51.9 years; 54.3% were women; and 52.4% were white; the mean follow-up period was 3.8 years.
The primary outcome was the association between depression diagnosis and severity on components of MetS at baseline and over a 4-year period. Participants were classified by MetS trajectory as recovered, incident, or persistent, and classified by depression status as without depression or with a mild, moderate, or severe current depressive episode. Depression status was based on the Clinical Interview Schedule Revised. MetS components and diagnosis were based on the National Cholesterol Education Program Adult Treatment Panel III.
In a logistic regression analysis, baseline depression was positively associated with recovered, incident, and persistent MetS (odds ratios, 1.59, 1.45, and 1.70, respectively).
Depression at baseline also was significantly associated with separate components of MetS: large waist circumference, high triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia, with odds ratios of 1.47, 1.23, 1.30, and 1.38, respectively.
Although not seen at baseline, a significant positive association between baseline depression and the presence of three or more MetS components was noted at follow-up, with a positive dose-response effect, the researchers wrote in their discussion.
Not all associations were statistically significant, but this was mainly because of the small number of cases of moderate and severe depression, they said. However, the magnitude of associations was greater in severe depression, when compared with moderate and mild, which suggests that the risk of MetS may be higher in this population, they added.
The study findings were limited by several factors including the possible misclassification of depression, inability to differentiate among depressive subtypes, and the potential lack of generalizability to other populations beyond Brazilian civil servants, the researchers noted.
However, the results were strengthened by the large sample size and support the role of depression as a risk factor for MetS, they said. More research is needed to determine a bidirectional relationship and to assess the trajectory of depression after MetS develops, but the findings “highlight the need to investigate and manage metabolic and cardiovascular alterations in the presence of depression in clinical settings,” they concluded.
The study was supported by the Brazilian Ministry of Health (Science and Technology Department) and the Brazilian Ministry of Science, Technology and Innovation FINEP and CNPq, and by the Coordenaçaõ de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES). The researchers had no financial conflicts to disclose.
Previous research has established a connection between metabolic syndrome and depression, but data on the increased risk for depressed individuals to develop metabolic syndrome (MetS) are lacking, wrote Lara Onofre Ferriani, PhD, of Federal University of Espírito Santo, Vitoria, Brazil, and colleagues.
“Individuals with MetS and depression have increased levels of inflammatory markers, and it is speculated that inflammation could mediate this comorbidity,” they said.
In a study published in the Journal of Psychiatric Research, the investigators reviewed data from 13,883 participants in the Brazilian Longitudinal Study of Adult Health; all were civil servants at universities in Brazil. The participants ranged from 35 to 74 years of age, with a mean age of 51.9 years; 54.3% were women; and 52.4% were white; the mean follow-up period was 3.8 years.
The primary outcome was the association between depression diagnosis and severity on components of MetS at baseline and over a 4-year period. Participants were classified by MetS trajectory as recovered, incident, or persistent, and classified by depression status as without depression or with a mild, moderate, or severe current depressive episode. Depression status was based on the Clinical Interview Schedule Revised. MetS components and diagnosis were based on the National Cholesterol Education Program Adult Treatment Panel III.
In a logistic regression analysis, baseline depression was positively associated with recovered, incident, and persistent MetS (odds ratios, 1.59, 1.45, and 1.70, respectively).
Depression at baseline also was significantly associated with separate components of MetS: large waist circumference, high triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia, with odds ratios of 1.47, 1.23, 1.30, and 1.38, respectively.
Although not seen at baseline, a significant positive association between baseline depression and the presence of three or more MetS components was noted at follow-up, with a positive dose-response effect, the researchers wrote in their discussion.
Not all associations were statistically significant, but this was mainly because of the small number of cases of moderate and severe depression, they said. However, the magnitude of associations was greater in severe depression, when compared with moderate and mild, which suggests that the risk of MetS may be higher in this population, they added.
The study findings were limited by several factors including the possible misclassification of depression, inability to differentiate among depressive subtypes, and the potential lack of generalizability to other populations beyond Brazilian civil servants, the researchers noted.
However, the results were strengthened by the large sample size and support the role of depression as a risk factor for MetS, they said. More research is needed to determine a bidirectional relationship and to assess the trajectory of depression after MetS develops, but the findings “highlight the need to investigate and manage metabolic and cardiovascular alterations in the presence of depression in clinical settings,” they concluded.
The study was supported by the Brazilian Ministry of Health (Science and Technology Department) and the Brazilian Ministry of Science, Technology and Innovation FINEP and CNPq, and by the Coordenaçaõ de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES). The researchers had no financial conflicts to disclose.
FROM THE JOURNAL OF PSYCHIATRIC RESEARCH
Vitamin D deficiency: Can we improve diagnosis?
CHICAGO – , new research suggests.
The study supports previous data suggesting that a ratio cut-off of greater than 100 is associated with the development of secondary hyperparathyroidism and the need for correction with supplementation, while a level greater than 50 suggests mild to moderate deficiency, Zhinous Shahidzadeh Yazdi, MD, noted in a poster presented at the annual meeting of the Endocrine Society
Current Endocrine Society guidelines published in 2011 advise measurement of plasma circulating 25(OH)D levels to evaluate vitamin D status in patients at risk for deficiency, defined as < 20 ng/mL (50 nmol/L). Revised guidelines are due out in early 2024.
“We don’t think measuring 25 hydroxy D is optimal because of the impact of vitamin D binding protein,” Dr. Yazdi said in an interview.
“Over 99% of all metabolites are bound to vitamin D binding protein, but only the free fraction is biologically active. By measuring total plasma 25(OH)D – as we do right now in clinic – we cannot account for the impact of vitamin D binding proteins, which vary by threefold across the population,” she added.
Thus, the total 25(OH)D deficiency cut-off of < 20 mg/mL currently recommended by the Endocrine Society may signal clinically significant vitamin D deficiency in one person but not another, noted Dr. Yazdi, a postdoctoral fellow at the University of Maryland, Baltimore.
Directly measuring binding protein or the free fraction would be ideal, but “there aren’t good commercial assays for those, and it’s more difficult to do. So, as an alternative, the vitamin D metabolite ratios implicitly adjust for individual differences in vitamin D binding protein,” she explained.
The ratio that Dr. Yazdi and colleagues propose to measure is that of the vitamin D metabolites 1,25(OH)2D/24,25 (OH)2D (shortened to 1,25D/24,25D), which they say reflect the body’s homeostatic response to vitamin D levels, and which rises in the setting of deficiency. It is a measurement > 100 in this ratio that they believe means the patient should receive vitamin D supplementation.
Controversial topic, ratio proposal is “very early in the game”
The issue of vitamin D deficiency has long generated controversy, particularly since publication of findings from the VITAL study in 2022, which showed vitamin D supplements did not significantly reduce the risk of fracture among adults in midlife and older compared with placebo.
According to the senior author of the new study, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, what still remains controversial after VITAL is the question: “How can you identify people who have sufficiently bad vitamin D deficiency that it’s adversely impacting their bones?”
He added that there is a suggestion that small subpopulations in VITAL really did benefit from vitamin D supplementation, but the study “wasn’t designed to look at that.”
Indeed, the authors of an editorial accompanying the publication of the VITAL study said the findings mean there is no justification for measuring 25(OH)D in the general population or for treating to a target level.
Asked to comment on Dr. Yazdi and colleagues’ ratio proposal for diagnosing vitamin D deficiency, the coauthor of the VITAL study editorial, Clifford J. Rosen, MD, said in an interview: “I do think it’s important to point out that changes in the vitamin D binding protein can have a significant impact on the level of 25 [OH] D ... People should recognize that.”
And, Dr. Rosen noted, “I like the idea that the ... [ratio] is a measure of what’s happening in the body in response to vitamin D stores. So, when you supplement, it comes back up ... In certain individuals at high risk for fractures, for example, you might want to consider a more extensive workup like they’re suggesting.”
However, Dr. Rosen, of the Rosen Musculoskeletal Laboratory at Maine Medical Center Research Institute, Scarborough, added: “If the 25[OH]D level is below 20 [ng/mL] you’re going to treat regardless. When we think about sensitivity, a 25[OH]D level less than 20 [ng/mL] is a good screen ... Those individuals need to be treated, especially if they have low bone mass or fractures.”
To validate the ratio for clinical use, Dr. Rosen said, larger numbers of individuals would need to be evaluated. Moreover, “you’d need to run a standard of vitamin D binding protein by mass spectrometry versus their assumed method using ratios. Ratios are always a little tricky to interpret. So, I think this is very early in the game.”
And measuring the ratio of 1,25D/24,25D “is quite expensive,” he added.
He also pointed out that “calcium intake is really critical. You can have a [25(OH)D] level of 18 ng/mL and not have any of those secondary changes because [you’re] taking adequate calcium ... So, that always is a consideration that has to be worked into the evaluation.”
Same 25(OH)D, different risk level
In their poster, Dr. Yazdi and colleagues explain that to assess vitamin D status “one needs to understand regulation of vitamin D metabolism.” 25(OH)D undergoes two alternative fates: 1α-hydroxylation in the kidney, generating 1,25D (the biologically active form) or 24-hydroxylation leading to 24,25D (a biologically inactive metabolite).
For their study, they analyzed pilot data from 11 otherwise healthy individuals who had total baseline plasma 25(OH)D levels < 20 ng/mL, and compared 25(OH)D, 1,25D, 24,25D, and parathyroid hormone before versus after treating them with vitamin D3 supplementation of 50,000 IU per week for 4-6 weeks, aiming for a total 25D level above 30 ng/mL.
They then modeled how the body maintains 1,25D in a normal range and calculated/compared two vitamin D metabolite ratios in vitamin D deficient versus sufficient states: 25(OH)D/1,25D and 1,25D/24,25D. They then evaluated the applicability of these ratios for assessment of vitamin D status.
They explained that suppression of 24-hydroxylase is the first line of defense to maintain 1,25D levels. Secondary hyperparathyroidism is the second line of defense and occurs in severe vitamin D deficiency when the first line is maximally deployed.
Overall, there was poor correlation between 25[OH]D and 1,25D, “consistent with previous evidence that in mild to moderate vitamin D deficiency, 1,25D is maintained in the normal range, and therefore not a useful index for assessing vitamin D status,” the researchers said in their poster.
Hence, they said, the need to add the ratio of 1,25D/24,25D.
They presented a comparison of two study participants: one with a baseline 25[OH]D of 12.3 ng/mL, the other of 11.7 ng/mL. Although both would therefore be classified as deficient according to current guidelines, their 1,25D/24,25D ratios were 20 and 110, respectively.
In the first participant, the parathyroid hormone response to vitamin D supplementation was negligible, at +5%, compared with a dramatic 34% drop in the second participant.
“We think only the one with very high 1,25D/24,25D [ratio of 110] and a significant drop in parathyroid hormone after vitamin D supplementation [-34%] was vitamin D deficient,” the researchers said.
However, Dr. Taylor noted: “The diagnostic cut-offs we describe should be viewed as tentative for the time being. Additional research will be required to fully validate the optimal diagnostic criteria.”
Dr. Yazdi and Dr. Rosen have reported no relevant financial relationships. Dr. Taylor has reported being a consultant for Ionis Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
CHICAGO – , new research suggests.
The study supports previous data suggesting that a ratio cut-off of greater than 100 is associated with the development of secondary hyperparathyroidism and the need for correction with supplementation, while a level greater than 50 suggests mild to moderate deficiency, Zhinous Shahidzadeh Yazdi, MD, noted in a poster presented at the annual meeting of the Endocrine Society
Current Endocrine Society guidelines published in 2011 advise measurement of plasma circulating 25(OH)D levels to evaluate vitamin D status in patients at risk for deficiency, defined as < 20 ng/mL (50 nmol/L). Revised guidelines are due out in early 2024.
“We don’t think measuring 25 hydroxy D is optimal because of the impact of vitamin D binding protein,” Dr. Yazdi said in an interview.
“Over 99% of all metabolites are bound to vitamin D binding protein, but only the free fraction is biologically active. By measuring total plasma 25(OH)D – as we do right now in clinic – we cannot account for the impact of vitamin D binding proteins, which vary by threefold across the population,” she added.
Thus, the total 25(OH)D deficiency cut-off of < 20 mg/mL currently recommended by the Endocrine Society may signal clinically significant vitamin D deficiency in one person but not another, noted Dr. Yazdi, a postdoctoral fellow at the University of Maryland, Baltimore.
Directly measuring binding protein or the free fraction would be ideal, but “there aren’t good commercial assays for those, and it’s more difficult to do. So, as an alternative, the vitamin D metabolite ratios implicitly adjust for individual differences in vitamin D binding protein,” she explained.
The ratio that Dr. Yazdi and colleagues propose to measure is that of the vitamin D metabolites 1,25(OH)2D/24,25 (OH)2D (shortened to 1,25D/24,25D), which they say reflect the body’s homeostatic response to vitamin D levels, and which rises in the setting of deficiency. It is a measurement > 100 in this ratio that they believe means the patient should receive vitamin D supplementation.
Controversial topic, ratio proposal is “very early in the game”
The issue of vitamin D deficiency has long generated controversy, particularly since publication of findings from the VITAL study in 2022, which showed vitamin D supplements did not significantly reduce the risk of fracture among adults in midlife and older compared with placebo.
According to the senior author of the new study, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, what still remains controversial after VITAL is the question: “How can you identify people who have sufficiently bad vitamin D deficiency that it’s adversely impacting their bones?”
He added that there is a suggestion that small subpopulations in VITAL really did benefit from vitamin D supplementation, but the study “wasn’t designed to look at that.”
Indeed, the authors of an editorial accompanying the publication of the VITAL study said the findings mean there is no justification for measuring 25(OH)D in the general population or for treating to a target level.
Asked to comment on Dr. Yazdi and colleagues’ ratio proposal for diagnosing vitamin D deficiency, the coauthor of the VITAL study editorial, Clifford J. Rosen, MD, said in an interview: “I do think it’s important to point out that changes in the vitamin D binding protein can have a significant impact on the level of 25 [OH] D ... People should recognize that.”
And, Dr. Rosen noted, “I like the idea that the ... [ratio] is a measure of what’s happening in the body in response to vitamin D stores. So, when you supplement, it comes back up ... In certain individuals at high risk for fractures, for example, you might want to consider a more extensive workup like they’re suggesting.”
However, Dr. Rosen, of the Rosen Musculoskeletal Laboratory at Maine Medical Center Research Institute, Scarborough, added: “If the 25[OH]D level is below 20 [ng/mL] you’re going to treat regardless. When we think about sensitivity, a 25[OH]D level less than 20 [ng/mL] is a good screen ... Those individuals need to be treated, especially if they have low bone mass or fractures.”
To validate the ratio for clinical use, Dr. Rosen said, larger numbers of individuals would need to be evaluated. Moreover, “you’d need to run a standard of vitamin D binding protein by mass spectrometry versus their assumed method using ratios. Ratios are always a little tricky to interpret. So, I think this is very early in the game.”
And measuring the ratio of 1,25D/24,25D “is quite expensive,” he added.
He also pointed out that “calcium intake is really critical. You can have a [25(OH)D] level of 18 ng/mL and not have any of those secondary changes because [you’re] taking adequate calcium ... So, that always is a consideration that has to be worked into the evaluation.”
Same 25(OH)D, different risk level
In their poster, Dr. Yazdi and colleagues explain that to assess vitamin D status “one needs to understand regulation of vitamin D metabolism.” 25(OH)D undergoes two alternative fates: 1α-hydroxylation in the kidney, generating 1,25D (the biologically active form) or 24-hydroxylation leading to 24,25D (a biologically inactive metabolite).
For their study, they analyzed pilot data from 11 otherwise healthy individuals who had total baseline plasma 25(OH)D levels < 20 ng/mL, and compared 25(OH)D, 1,25D, 24,25D, and parathyroid hormone before versus after treating them with vitamin D3 supplementation of 50,000 IU per week for 4-6 weeks, aiming for a total 25D level above 30 ng/mL.
They then modeled how the body maintains 1,25D in a normal range and calculated/compared two vitamin D metabolite ratios in vitamin D deficient versus sufficient states: 25(OH)D/1,25D and 1,25D/24,25D. They then evaluated the applicability of these ratios for assessment of vitamin D status.
They explained that suppression of 24-hydroxylase is the first line of defense to maintain 1,25D levels. Secondary hyperparathyroidism is the second line of defense and occurs in severe vitamin D deficiency when the first line is maximally deployed.
Overall, there was poor correlation between 25[OH]D and 1,25D, “consistent with previous evidence that in mild to moderate vitamin D deficiency, 1,25D is maintained in the normal range, and therefore not a useful index for assessing vitamin D status,” the researchers said in their poster.
Hence, they said, the need to add the ratio of 1,25D/24,25D.
They presented a comparison of two study participants: one with a baseline 25[OH]D of 12.3 ng/mL, the other of 11.7 ng/mL. Although both would therefore be classified as deficient according to current guidelines, their 1,25D/24,25D ratios were 20 and 110, respectively.
In the first participant, the parathyroid hormone response to vitamin D supplementation was negligible, at +5%, compared with a dramatic 34% drop in the second participant.
“We think only the one with very high 1,25D/24,25D [ratio of 110] and a significant drop in parathyroid hormone after vitamin D supplementation [-34%] was vitamin D deficient,” the researchers said.
However, Dr. Taylor noted: “The diagnostic cut-offs we describe should be viewed as tentative for the time being. Additional research will be required to fully validate the optimal diagnostic criteria.”
Dr. Yazdi and Dr. Rosen have reported no relevant financial relationships. Dr. Taylor has reported being a consultant for Ionis Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
CHICAGO – , new research suggests.
The study supports previous data suggesting that a ratio cut-off of greater than 100 is associated with the development of secondary hyperparathyroidism and the need for correction with supplementation, while a level greater than 50 suggests mild to moderate deficiency, Zhinous Shahidzadeh Yazdi, MD, noted in a poster presented at the annual meeting of the Endocrine Society
Current Endocrine Society guidelines published in 2011 advise measurement of plasma circulating 25(OH)D levels to evaluate vitamin D status in patients at risk for deficiency, defined as < 20 ng/mL (50 nmol/L). Revised guidelines are due out in early 2024.
“We don’t think measuring 25 hydroxy D is optimal because of the impact of vitamin D binding protein,” Dr. Yazdi said in an interview.
“Over 99% of all metabolites are bound to vitamin D binding protein, but only the free fraction is biologically active. By measuring total plasma 25(OH)D – as we do right now in clinic – we cannot account for the impact of vitamin D binding proteins, which vary by threefold across the population,” she added.
Thus, the total 25(OH)D deficiency cut-off of < 20 mg/mL currently recommended by the Endocrine Society may signal clinically significant vitamin D deficiency in one person but not another, noted Dr. Yazdi, a postdoctoral fellow at the University of Maryland, Baltimore.
Directly measuring binding protein or the free fraction would be ideal, but “there aren’t good commercial assays for those, and it’s more difficult to do. So, as an alternative, the vitamin D metabolite ratios implicitly adjust for individual differences in vitamin D binding protein,” she explained.
The ratio that Dr. Yazdi and colleagues propose to measure is that of the vitamin D metabolites 1,25(OH)2D/24,25 (OH)2D (shortened to 1,25D/24,25D), which they say reflect the body’s homeostatic response to vitamin D levels, and which rises in the setting of deficiency. It is a measurement > 100 in this ratio that they believe means the patient should receive vitamin D supplementation.
Controversial topic, ratio proposal is “very early in the game”
The issue of vitamin D deficiency has long generated controversy, particularly since publication of findings from the VITAL study in 2022, which showed vitamin D supplements did not significantly reduce the risk of fracture among adults in midlife and older compared with placebo.
According to the senior author of the new study, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, what still remains controversial after VITAL is the question: “How can you identify people who have sufficiently bad vitamin D deficiency that it’s adversely impacting their bones?”
He added that there is a suggestion that small subpopulations in VITAL really did benefit from vitamin D supplementation, but the study “wasn’t designed to look at that.”
Indeed, the authors of an editorial accompanying the publication of the VITAL study said the findings mean there is no justification for measuring 25(OH)D in the general population or for treating to a target level.
Asked to comment on Dr. Yazdi and colleagues’ ratio proposal for diagnosing vitamin D deficiency, the coauthor of the VITAL study editorial, Clifford J. Rosen, MD, said in an interview: “I do think it’s important to point out that changes in the vitamin D binding protein can have a significant impact on the level of 25 [OH] D ... People should recognize that.”
And, Dr. Rosen noted, “I like the idea that the ... [ratio] is a measure of what’s happening in the body in response to vitamin D stores. So, when you supplement, it comes back up ... In certain individuals at high risk for fractures, for example, you might want to consider a more extensive workup like they’re suggesting.”
However, Dr. Rosen, of the Rosen Musculoskeletal Laboratory at Maine Medical Center Research Institute, Scarborough, added: “If the 25[OH]D level is below 20 [ng/mL] you’re going to treat regardless. When we think about sensitivity, a 25[OH]D level less than 20 [ng/mL] is a good screen ... Those individuals need to be treated, especially if they have low bone mass or fractures.”
To validate the ratio for clinical use, Dr. Rosen said, larger numbers of individuals would need to be evaluated. Moreover, “you’d need to run a standard of vitamin D binding protein by mass spectrometry versus their assumed method using ratios. Ratios are always a little tricky to interpret. So, I think this is very early in the game.”
And measuring the ratio of 1,25D/24,25D “is quite expensive,” he added.
He also pointed out that “calcium intake is really critical. You can have a [25(OH)D] level of 18 ng/mL and not have any of those secondary changes because [you’re] taking adequate calcium ... So, that always is a consideration that has to be worked into the evaluation.”
Same 25(OH)D, different risk level
In their poster, Dr. Yazdi and colleagues explain that to assess vitamin D status “one needs to understand regulation of vitamin D metabolism.” 25(OH)D undergoes two alternative fates: 1α-hydroxylation in the kidney, generating 1,25D (the biologically active form) or 24-hydroxylation leading to 24,25D (a biologically inactive metabolite).
For their study, they analyzed pilot data from 11 otherwise healthy individuals who had total baseline plasma 25(OH)D levels < 20 ng/mL, and compared 25(OH)D, 1,25D, 24,25D, and parathyroid hormone before versus after treating them with vitamin D3 supplementation of 50,000 IU per week for 4-6 weeks, aiming for a total 25D level above 30 ng/mL.
They then modeled how the body maintains 1,25D in a normal range and calculated/compared two vitamin D metabolite ratios in vitamin D deficient versus sufficient states: 25(OH)D/1,25D and 1,25D/24,25D. They then evaluated the applicability of these ratios for assessment of vitamin D status.
They explained that suppression of 24-hydroxylase is the first line of defense to maintain 1,25D levels. Secondary hyperparathyroidism is the second line of defense and occurs in severe vitamin D deficiency when the first line is maximally deployed.
Overall, there was poor correlation between 25[OH]D and 1,25D, “consistent with previous evidence that in mild to moderate vitamin D deficiency, 1,25D is maintained in the normal range, and therefore not a useful index for assessing vitamin D status,” the researchers said in their poster.
Hence, they said, the need to add the ratio of 1,25D/24,25D.
They presented a comparison of two study participants: one with a baseline 25[OH]D of 12.3 ng/mL, the other of 11.7 ng/mL. Although both would therefore be classified as deficient according to current guidelines, their 1,25D/24,25D ratios were 20 and 110, respectively.
In the first participant, the parathyroid hormone response to vitamin D supplementation was negligible, at +5%, compared with a dramatic 34% drop in the second participant.
“We think only the one with very high 1,25D/24,25D [ratio of 110] and a significant drop in parathyroid hormone after vitamin D supplementation [-34%] was vitamin D deficient,” the researchers said.
However, Dr. Taylor noted: “The diagnostic cut-offs we describe should be viewed as tentative for the time being. Additional research will be required to fully validate the optimal diagnostic criteria.”
Dr. Yazdi and Dr. Rosen have reported no relevant financial relationships. Dr. Taylor has reported being a consultant for Ionis Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
AT ENDO 2023