Endocrinology

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

“No one has asked young people what they want,” said Tabitha Randell, MBChB, an endocrinologist with Nottingham (England) University Hospitals NHS Trust, who specializes in treating teenagers with type 1 diabetes as they transition to adult care.

Dr. Randell, who has set up a very successful specialist service in her hospital for such patients, said: “We consistently have the best, or the second best, outcomes in this country for our diabetes patients.” She believes this is one of the most important issues in modern endocrinology today.

Speaking at the Diabetes Professional Care conference in London at the end of 2021, and sharing her thoughts afterward with this news organization, she noted that in general there are “virtually no published outcomes” on how best to transition a patient with type 1 diabetes from pediatric to adult care.

“If you actually get them to transition – because some just drop out and disengage and there’s nothing you can do – none of them get lost. Some of them disengage in the adult clinic, but if you’re in the young diabetes service [in England] the rules are that if you miss a diabetes appointment you do not get discharged, as compared with the adult clinic, where if you miss an appointment, you are discharged.”

In the young diabetes clinic, doctors will “carry on trying to contact you, and get you back,” she explained. “And the patients do eventually come back in – it might be a year or 2, but they do come back. We’ve just got to keep them alive in the meantime!”

This issue needs tackling all over the world. Dr. Randell said she’s not aware of any one country – although there may be “pockets” of good care within a given country – that is doing this perfectly.

Across the pond, Grazia Aleppo, MD, division of endocrinology at Northwestern University, Chicago, agreed that transitioning pediatric patients with type 1 diabetes to adult care presents “unique challenges.”
 

Challenges when transitioning from pediatric to adult care

During childhood, type 1 diabetes management is largely supervised by patients’ parents and members of the pediatric diabetes care team, which may include diabetes educators, psychologists, or social workers, as well as pediatric endocrinologists.

When the patient with type 1 diabetes becomes a young adult and takes over management of their own health, Dr. Aleppo said, the care team may diminish along with the time spent in provider visits.

The adult endocrinology setting focuses more on self-management and autonomous functioning of the individual with diabetes.

Adult appointments are typically shorter, and the patient is usually expected to follow doctors’ suggestions independently, she noted. They are also expected to manage the practical aspects of their diabetes care, including prescriptions, diabetes supplies, laboratory tests, scheduling, and keeping appointments.

At the same time that the emerging adult needs to start asserting independence over their health care, they will also be going through a myriad of other important lifestyle changes, such as attending college, living on their own for the first time, and starting a career.  

“With these fundamental differences and challenges, competing priorities, such as college, work and relationships, medical care may become of secondary importance and patients may become disengaged,” Dr. Aleppo explained.

As Dr. Randell has said, loss to follow-up is a big problem with this patient population, with disengagement from specialist services and worsening A1c across the transition, Dr. Aleppo noted. This makes addressing these patients’ specific needs extremely important.
 

Engage with kid, not disease; don’t palm them off on new recruits

“The really key thing these kids say is, ‘I do not want to be a disease,’” Dr. Randell said. “They want you to know that they are a person. Engage these kids!” she suggested. “Ask them: ‘How is your exam revision going?’ Find something positive to say, even if it’s just: ‘I’m glad you came today.’ ”

“If the first thing that you do is tell them off [for poor diabetes care], you are never going to see them again,” she cautioned.

Dr. Randell also said that role models with type 1 diabetes, such as Lila Moss – daughter of British supermodel Kate Moss – who was recently pictured wearing an insulin pump on her leg on the catwalk, are helping youngsters not feel so self-conscious about their diabetes.

“Let them know it’s not the end of the world, having [type 1] diabetes,” she emphasized.  

And Partha Kar, MBBS, OBE, national specialty advisor, diabetes with NHS England, agreed wholeheartedly with Dr. Randall.

Reminiscing about his early days as a newly qualified endocrinologist, Dr. Kar, who works at Portsmouth (England) Hospital NHS Trust, noted that as a new member of staff he was given the youth with type 1 diabetes – those getting ready to transition to adult care – to look after.

But this is the exact opposite of what should be happening, he emphasized. “If you don’t think transition care is important, you shouldn’t be treating type 1 diabetes.”

He believes that every diabetes center “must have a young-adult team lead” and this job must not be given to the least experienced member of staff.

This lead “doesn’t need to be a doctor,” Dr. Kar stressed. “It can be a psychologist, or a diabetes nurse, or a pharmacist, or a dietician.”

In short, it must be someone experienced who loves working with this age group.  

Dr. Randell agreed: “Make sure the team is interested in young people. It shouldn’t be the last person in who gets the job no one else wants.” Teens “are my favorite group to work with. They don’t take any nonsense.”

And she explained: “Young people like to get to know the person who’s going to take care of them. So, stay with them for their young adult years.” This can be “quite a fluid period,” with it normally extending to age 25, but in some cases, “it can be up to 32 years old.”
 

Preparing for the transition

To ease pediatric patients into the transition to adult care, Dr. Aleppo recommended that the pediatric diabetes team provide enough time so that any concerns the patient and their family may have can be addressed.

This should also include transferring management responsibilities to the young adult rather than their parent.

The pediatric provider should discuss with the patient available potential adult colleagues, personalizing these options to their needs, she said.

And the adult and pediatric clinicians should collaborate and provide important information beyond medical records or health summaries.

Adult providers should guide young adults on how to navigate the new practices, from scheduling follow-up appointments to policies regarding medication refills or supplies, to providing information about urgent numbers or email addresses for after-hours communications.

Dr. Kar reiterated that there are too few published outcomes in this patient group to guide the establishment of good transition services.

“Without data, we are dead on the ground. Without data, it’s all conjecture, anecdotes,” he said.

What he does know is that, in the latest national type 1 diabetes audit for England, “Diabetic ketoacidosis admissions ... are up in this age group,” which suggests these patients are not receiving adequate care.
 

Be a guide, not a gatekeeper

Dr. Kar stressed that, of the 8,760 hours in a year, the average patient with type 1 diabetes in the United Kingdom gets just “1-2 hours with you as a clinician, based on four appointments per year of 30 minutes each.”

“So you spend 0.02% of their time with individuals with type 1 diabetes. So, what’s the one thing you can do with that minimal contact? Be nice!”

Dr. Kar said he always has his email open to his adult patients and they are very respectful of his time. “They don’t email you at 1 a.m. That means every one of my patients has got support [from me]. Don’t be a barrier.”

“We have to fundamentally change the narrative. Doctors must have more empathy,” he said, stating that the one thing adolescents have constantly given feedback on has been, “Why don’t appointments start with: ‘How are you?’ 

“For a teenager, if you throw type 1 diabetes into the loop, it’s not easy,” he stressed. “Talk to them about something else. As a clinician, be a guide, not a gatekeeper. Give people the tools to self-manage better.”

Adult providers can meet these young adult patients “at their level,” Dr. Aleppo agreed.

“Pay attention to their immediate needs and focus on their present circumstances – whether how to get through their next semester in college, navigating job interviews, or handling having diabetes in the workplace.”

Paying attention to the mental health needs of these young patients is equally “paramount,” Dr. Aleppo said.

While access to mental health professionals may be challenging in the adult setting, providers should bring it up with their patients and offer counseling referrals.

“Diabetes impacts everything, and office appointments and conversations carry weight on these patients’ lives as a whole, not just on their diabetes,” she stressed. “A patient told me recently: ‘We’re learning to be adults,’ which can be hard enough, and with diabetes it can be even more challenging. Adult providers need to be aware of the patient’s ‘diabetes language’ in that often it is not what a patient is saying, rather how they are saying it that gives us information on what they truly need.

“As adult providers, we need to also train and teach our young patients to advocate for themselves on where to find resources that can help them navigate adulthood with diabetes,” she added.

One particularly helpful resource in the United States is the College Diabetes Network, a not-for-profit organization whose mission is to equip young adults with type 1 diabetes to successfully manage the challenging transition to independence at college and beyond.

“The sweetest thing that can happen to us as adult diabetes providers is when a patient – seen as an emerging adult during college – returns to your practice 10 years later after moving back and seeks you out for their diabetes care because of the relationship and trust you developed in those transitioning years,” Dr. Aleppo said.

Another resource is a freely available comic book series cocreated by Dr. Kar and colleague Mayank Patel, MBBS, an endocrinologist from University Hospital Southampton NHS Foundation Trust.

As detailed by this news organization in 2021, the series consists of three volumes: the first, Type 1: Origins, focuses on actual experiences of patients who have type 1 diabetes; the second, Type 1: Attack of the Ketones, is aimed at professionals who may provide care but have limited understanding of type 1 diabetes; and the third, Type 1 Mission 3: S.T.I.G.M.A., addresses the stigmas and misconceptions that patients with type 1 diabetes may face.

The idea for the first comic was inspired by a patient who compared having diabetes to being like the Marvel character The Hulk, said Dr. Kar, and has been expanded to include the additional volumes.

Dr. Kar and Dr. Patel have also just launched the fourth comic in the series, Type 1: Generations, to mark the 100-year anniversary since insulin was first given to a human.
 

“This is high priority”  

Dr. Kar said the NHS in England has just appointed a national lead for type 1 diabetes in youth, Fulya Mehta, MD, of Alder Hey Children’s NHS Foundation Trust, Liverpool, England.

“If you have a plan, bring it to us,” he told the audience at the DPC conference, and “tell us, what is the one thing you would change? This is not a session we are doing just to tick a box. This is high priority.

“Encourage your colleagues to think about transition services. This is an absolute priority. We will be asking every center [in England] who is your transitioning lead?”

And he once again stressed that “a lead of transition service does not have to be a medic. This should be a multidisciplinary team. But they do need to be comfortable in that space. To that teenager, your job title means nothing. Give them time and space.”

Dr. Randell summed it up: “If we can work together, it’s only going to result in better outcomes. We need to blaze the trail for young people.”

Dr. Aleppo has reported serving as a consultant to Dexcom and Insulet and receiving support to Northwestern University from AstraZeneca, Dexcom, Eli Lilly, Fractyl Health, Insulet, and Novo Nordisk. Dr. Randell and Dr. Kar have no conflicts of interest.

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

“No one has asked young people what they want,” said Tabitha Randell, MBChB, an endocrinologist with Nottingham (England) University Hospitals NHS Trust, who specializes in treating teenagers with type 1 diabetes as they transition to adult care.

Dr. Randell, who has set up a very successful specialist service in her hospital for such patients, said: “We consistently have the best, or the second best, outcomes in this country for our diabetes patients.” She believes this is one of the most important issues in modern endocrinology today.

Speaking at the Diabetes Professional Care conference in London at the end of 2021, and sharing her thoughts afterward with this news organization, she noted that in general there are “virtually no published outcomes” on how best to transition a patient with type 1 diabetes from pediatric to adult care.

“If you actually get them to transition – because some just drop out and disengage and there’s nothing you can do – none of them get lost. Some of them disengage in the adult clinic, but if you’re in the young diabetes service [in England] the rules are that if you miss a diabetes appointment you do not get discharged, as compared with the adult clinic, where if you miss an appointment, you are discharged.”

In the young diabetes clinic, doctors will “carry on trying to contact you, and get you back,” she explained. “And the patients do eventually come back in – it might be a year or 2, but they do come back. We’ve just got to keep them alive in the meantime!”

This issue needs tackling all over the world. Dr. Randell said she’s not aware of any one country – although there may be “pockets” of good care within a given country – that is doing this perfectly.

Across the pond, Grazia Aleppo, MD, division of endocrinology at Northwestern University, Chicago, agreed that transitioning pediatric patients with type 1 diabetes to adult care presents “unique challenges.”
 

Challenges when transitioning from pediatric to adult care

During childhood, type 1 diabetes management is largely supervised by patients’ parents and members of the pediatric diabetes care team, which may include diabetes educators, psychologists, or social workers, as well as pediatric endocrinologists.

When the patient with type 1 diabetes becomes a young adult and takes over management of their own health, Dr. Aleppo said, the care team may diminish along with the time spent in provider visits.

The adult endocrinology setting focuses more on self-management and autonomous functioning of the individual with diabetes.

Adult appointments are typically shorter, and the patient is usually expected to follow doctors’ suggestions independently, she noted. They are also expected to manage the practical aspects of their diabetes care, including prescriptions, diabetes supplies, laboratory tests, scheduling, and keeping appointments.

At the same time that the emerging adult needs to start asserting independence over their health care, they will also be going through a myriad of other important lifestyle changes, such as attending college, living on their own for the first time, and starting a career.  

“With these fundamental differences and challenges, competing priorities, such as college, work and relationships, medical care may become of secondary importance and patients may become disengaged,” Dr. Aleppo explained.

As Dr. Randell has said, loss to follow-up is a big problem with this patient population, with disengagement from specialist services and worsening A1c across the transition, Dr. Aleppo noted. This makes addressing these patients’ specific needs extremely important.
 

Engage with kid, not disease; don’t palm them off on new recruits

“The really key thing these kids say is, ‘I do not want to be a disease,’” Dr. Randell said. “They want you to know that they are a person. Engage these kids!” she suggested. “Ask them: ‘How is your exam revision going?’ Find something positive to say, even if it’s just: ‘I’m glad you came today.’ ”

“If the first thing that you do is tell them off [for poor diabetes care], you are never going to see them again,” she cautioned.

Dr. Randell also said that role models with type 1 diabetes, such as Lila Moss – daughter of British supermodel Kate Moss – who was recently pictured wearing an insulin pump on her leg on the catwalk, are helping youngsters not feel so self-conscious about their diabetes.

“Let them know it’s not the end of the world, having [type 1] diabetes,” she emphasized.  

And Partha Kar, MBBS, OBE, national specialty advisor, diabetes with NHS England, agreed wholeheartedly with Dr. Randall.

Reminiscing about his early days as a newly qualified endocrinologist, Dr. Kar, who works at Portsmouth (England) Hospital NHS Trust, noted that as a new member of staff he was given the youth with type 1 diabetes – those getting ready to transition to adult care – to look after.

But this is the exact opposite of what should be happening, he emphasized. “If you don’t think transition care is important, you shouldn’t be treating type 1 diabetes.”

He believes that every diabetes center “must have a young-adult team lead” and this job must not be given to the least experienced member of staff.

This lead “doesn’t need to be a doctor,” Dr. Kar stressed. “It can be a psychologist, or a diabetes nurse, or a pharmacist, or a dietician.”

In short, it must be someone experienced who loves working with this age group.  

Dr. Randell agreed: “Make sure the team is interested in young people. It shouldn’t be the last person in who gets the job no one else wants.” Teens “are my favorite group to work with. They don’t take any nonsense.”

And she explained: “Young people like to get to know the person who’s going to take care of them. So, stay with them for their young adult years.” This can be “quite a fluid period,” with it normally extending to age 25, but in some cases, “it can be up to 32 years old.”
 

Preparing for the transition

To ease pediatric patients into the transition to adult care, Dr. Aleppo recommended that the pediatric diabetes team provide enough time so that any concerns the patient and their family may have can be addressed.

This should also include transferring management responsibilities to the young adult rather than their parent.

The pediatric provider should discuss with the patient available potential adult colleagues, personalizing these options to their needs, she said.

And the adult and pediatric clinicians should collaborate and provide important information beyond medical records or health summaries.

Adult providers should guide young adults on how to navigate the new practices, from scheduling follow-up appointments to policies regarding medication refills or supplies, to providing information about urgent numbers or email addresses for after-hours communications.

Dr. Kar reiterated that there are too few published outcomes in this patient group to guide the establishment of good transition services.

“Without data, we are dead on the ground. Without data, it’s all conjecture, anecdotes,” he said.

What he does know is that, in the latest national type 1 diabetes audit for England, “Diabetic ketoacidosis admissions ... are up in this age group,” which suggests these patients are not receiving adequate care.
 

Be a guide, not a gatekeeper

Dr. Kar stressed that, of the 8,760 hours in a year, the average patient with type 1 diabetes in the United Kingdom gets just “1-2 hours with you as a clinician, based on four appointments per year of 30 minutes each.”

“So you spend 0.02% of their time with individuals with type 1 diabetes. So, what’s the one thing you can do with that minimal contact? Be nice!”

Dr. Kar said he always has his email open to his adult patients and they are very respectful of his time. “They don’t email you at 1 a.m. That means every one of my patients has got support [from me]. Don’t be a barrier.”

“We have to fundamentally change the narrative. Doctors must have more empathy,” he said, stating that the one thing adolescents have constantly given feedback on has been, “Why don’t appointments start with: ‘How are you?’ 

“For a teenager, if you throw type 1 diabetes into the loop, it’s not easy,” he stressed. “Talk to them about something else. As a clinician, be a guide, not a gatekeeper. Give people the tools to self-manage better.”

Adult providers can meet these young adult patients “at their level,” Dr. Aleppo agreed.

“Pay attention to their immediate needs and focus on their present circumstances – whether how to get through their next semester in college, navigating job interviews, or handling having diabetes in the workplace.”

Paying attention to the mental health needs of these young patients is equally “paramount,” Dr. Aleppo said.

While access to mental health professionals may be challenging in the adult setting, providers should bring it up with their patients and offer counseling referrals.

“Diabetes impacts everything, and office appointments and conversations carry weight on these patients’ lives as a whole, not just on their diabetes,” she stressed. “A patient told me recently: ‘We’re learning to be adults,’ which can be hard enough, and with diabetes it can be even more challenging. Adult providers need to be aware of the patient’s ‘diabetes language’ in that often it is not what a patient is saying, rather how they are saying it that gives us information on what they truly need.

“As adult providers, we need to also train and teach our young patients to advocate for themselves on where to find resources that can help them navigate adulthood with diabetes,” she added.

One particularly helpful resource in the United States is the College Diabetes Network, a not-for-profit organization whose mission is to equip young adults with type 1 diabetes to successfully manage the challenging transition to independence at college and beyond.

“The sweetest thing that can happen to us as adult diabetes providers is when a patient – seen as an emerging adult during college – returns to your practice 10 years later after moving back and seeks you out for their diabetes care because of the relationship and trust you developed in those transitioning years,” Dr. Aleppo said.

Another resource is a freely available comic book series cocreated by Dr. Kar and colleague Mayank Patel, MBBS, an endocrinologist from University Hospital Southampton NHS Foundation Trust.

As detailed by this news organization in 2021, the series consists of three volumes: the first, Type 1: Origins, focuses on actual experiences of patients who have type 1 diabetes; the second, Type 1: Attack of the Ketones, is aimed at professionals who may provide care but have limited understanding of type 1 diabetes; and the third, Type 1 Mission 3: S.T.I.G.M.A., addresses the stigmas and misconceptions that patients with type 1 diabetes may face.

The idea for the first comic was inspired by a patient who compared having diabetes to being like the Marvel character The Hulk, said Dr. Kar, and has been expanded to include the additional volumes.

Dr. Kar and Dr. Patel have also just launched the fourth comic in the series, Type 1: Generations, to mark the 100-year anniversary since insulin was first given to a human.
 

“This is high priority”  

Dr. Kar said the NHS in England has just appointed a national lead for type 1 diabetes in youth, Fulya Mehta, MD, of Alder Hey Children’s NHS Foundation Trust, Liverpool, England.

“If you have a plan, bring it to us,” he told the audience at the DPC conference, and “tell us, what is the one thing you would change? This is not a session we are doing just to tick a box. This is high priority.

“Encourage your colleagues to think about transition services. This is an absolute priority. We will be asking every center [in England] who is your transitioning lead?”

And he once again stressed that “a lead of transition service does not have to be a medic. This should be a multidisciplinary team. But they do need to be comfortable in that space. To that teenager, your job title means nothing. Give them time and space.”

Dr. Randell summed it up: “If we can work together, it’s only going to result in better outcomes. We need to blaze the trail for young people.”

Dr. Aleppo has reported serving as a consultant to Dexcom and Insulet and receiving support to Northwestern University from AstraZeneca, Dexcom, Eli Lilly, Fractyl Health, Insulet, and Novo Nordisk. Dr. Randell and Dr. Kar have no conflicts of interest.

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

“No one has asked young people what they want,” said Tabitha Randell, MBChB, an endocrinologist with Nottingham (England) University Hospitals NHS Trust, who specializes in treating teenagers with type 1 diabetes as they transition to adult care.

Dr. Randell, who has set up a very successful specialist service in her hospital for such patients, said: “We consistently have the best, or the second best, outcomes in this country for our diabetes patients.” She believes this is one of the most important issues in modern endocrinology today.

Speaking at the Diabetes Professional Care conference in London at the end of 2021, and sharing her thoughts afterward with this news organization, she noted that in general there are “virtually no published outcomes” on how best to transition a patient with type 1 diabetes from pediatric to adult care.

“If you actually get them to transition – because some just drop out and disengage and there’s nothing you can do – none of them get lost. Some of them disengage in the adult clinic, but if you’re in the young diabetes service [in England] the rules are that if you miss a diabetes appointment you do not get discharged, as compared with the adult clinic, where if you miss an appointment, you are discharged.”

In the young diabetes clinic, doctors will “carry on trying to contact you, and get you back,” she explained. “And the patients do eventually come back in – it might be a year or 2, but they do come back. We’ve just got to keep them alive in the meantime!”

This issue needs tackling all over the world. Dr. Randell said she’s not aware of any one country – although there may be “pockets” of good care within a given country – that is doing this perfectly.

Across the pond, Grazia Aleppo, MD, division of endocrinology at Northwestern University, Chicago, agreed that transitioning pediatric patients with type 1 diabetes to adult care presents “unique challenges.”
 

Challenges when transitioning from pediatric to adult care

During childhood, type 1 diabetes management is largely supervised by patients’ parents and members of the pediatric diabetes care team, which may include diabetes educators, psychologists, or social workers, as well as pediatric endocrinologists.

When the patient with type 1 diabetes becomes a young adult and takes over management of their own health, Dr. Aleppo said, the care team may diminish along with the time spent in provider visits.

The adult endocrinology setting focuses more on self-management and autonomous functioning of the individual with diabetes.

Adult appointments are typically shorter, and the patient is usually expected to follow doctors’ suggestions independently, she noted. They are also expected to manage the practical aspects of their diabetes care, including prescriptions, diabetes supplies, laboratory tests, scheduling, and keeping appointments.

At the same time that the emerging adult needs to start asserting independence over their health care, they will also be going through a myriad of other important lifestyle changes, such as attending college, living on their own for the first time, and starting a career.  

“With these fundamental differences and challenges, competing priorities, such as college, work and relationships, medical care may become of secondary importance and patients may become disengaged,” Dr. Aleppo explained.

As Dr. Randell has said, loss to follow-up is a big problem with this patient population, with disengagement from specialist services and worsening A1c across the transition, Dr. Aleppo noted. This makes addressing these patients’ specific needs extremely important.
 

Engage with kid, not disease; don’t palm them off on new recruits

“The really key thing these kids say is, ‘I do not want to be a disease,’” Dr. Randell said. “They want you to know that they are a person. Engage these kids!” she suggested. “Ask them: ‘How is your exam revision going?’ Find something positive to say, even if it’s just: ‘I’m glad you came today.’ ”

“If the first thing that you do is tell them off [for poor diabetes care], you are never going to see them again,” she cautioned.

Dr. Randell also said that role models with type 1 diabetes, such as Lila Moss – daughter of British supermodel Kate Moss – who was recently pictured wearing an insulin pump on her leg on the catwalk, are helping youngsters not feel so self-conscious about their diabetes.

“Let them know it’s not the end of the world, having [type 1] diabetes,” she emphasized.  

And Partha Kar, MBBS, OBE, national specialty advisor, diabetes with NHS England, agreed wholeheartedly with Dr. Randall.

Reminiscing about his early days as a newly qualified endocrinologist, Dr. Kar, who works at Portsmouth (England) Hospital NHS Trust, noted that as a new member of staff he was given the youth with type 1 diabetes – those getting ready to transition to adult care – to look after.

But this is the exact opposite of what should be happening, he emphasized. “If you don’t think transition care is important, you shouldn’t be treating type 1 diabetes.”

He believes that every diabetes center “must have a young-adult team lead” and this job must not be given to the least experienced member of staff.

This lead “doesn’t need to be a doctor,” Dr. Kar stressed. “It can be a psychologist, or a diabetes nurse, or a pharmacist, or a dietician.”

In short, it must be someone experienced who loves working with this age group.  

Dr. Randell agreed: “Make sure the team is interested in young people. It shouldn’t be the last person in who gets the job no one else wants.” Teens “are my favorite group to work with. They don’t take any nonsense.”

And she explained: “Young people like to get to know the person who’s going to take care of them. So, stay with them for their young adult years.” This can be “quite a fluid period,” with it normally extending to age 25, but in some cases, “it can be up to 32 years old.”
 

Preparing for the transition

To ease pediatric patients into the transition to adult care, Dr. Aleppo recommended that the pediatric diabetes team provide enough time so that any concerns the patient and their family may have can be addressed.

This should also include transferring management responsibilities to the young adult rather than their parent.

The pediatric provider should discuss with the patient available potential adult colleagues, personalizing these options to their needs, she said.

And the adult and pediatric clinicians should collaborate and provide important information beyond medical records or health summaries.

Adult providers should guide young adults on how to navigate the new practices, from scheduling follow-up appointments to policies regarding medication refills or supplies, to providing information about urgent numbers or email addresses for after-hours communications.

Dr. Kar reiterated that there are too few published outcomes in this patient group to guide the establishment of good transition services.

“Without data, we are dead on the ground. Without data, it’s all conjecture, anecdotes,” he said.

What he does know is that, in the latest national type 1 diabetes audit for England, “Diabetic ketoacidosis admissions ... are up in this age group,” which suggests these patients are not receiving adequate care.
 

Be a guide, not a gatekeeper

Dr. Kar stressed that, of the 8,760 hours in a year, the average patient with type 1 diabetes in the United Kingdom gets just “1-2 hours with you as a clinician, based on four appointments per year of 30 minutes each.”

“So you spend 0.02% of their time with individuals with type 1 diabetes. So, what’s the one thing you can do with that minimal contact? Be nice!”

Dr. Kar said he always has his email open to his adult patients and they are very respectful of his time. “They don’t email you at 1 a.m. That means every one of my patients has got support [from me]. Don’t be a barrier.”

“We have to fundamentally change the narrative. Doctors must have more empathy,” he said, stating that the one thing adolescents have constantly given feedback on has been, “Why don’t appointments start with: ‘How are you?’ 

“For a teenager, if you throw type 1 diabetes into the loop, it’s not easy,” he stressed. “Talk to them about something else. As a clinician, be a guide, not a gatekeeper. Give people the tools to self-manage better.”

Adult providers can meet these young adult patients “at their level,” Dr. Aleppo agreed.

“Pay attention to their immediate needs and focus on their present circumstances – whether how to get through their next semester in college, navigating job interviews, or handling having diabetes in the workplace.”

Paying attention to the mental health needs of these young patients is equally “paramount,” Dr. Aleppo said.

While access to mental health professionals may be challenging in the adult setting, providers should bring it up with their patients and offer counseling referrals.

“Diabetes impacts everything, and office appointments and conversations carry weight on these patients’ lives as a whole, not just on their diabetes,” she stressed. “A patient told me recently: ‘We’re learning to be adults,’ which can be hard enough, and with diabetes it can be even more challenging. Adult providers need to be aware of the patient’s ‘diabetes language’ in that often it is not what a patient is saying, rather how they are saying it that gives us information on what they truly need.

“As adult providers, we need to also train and teach our young patients to advocate for themselves on where to find resources that can help them navigate adulthood with diabetes,” she added.

One particularly helpful resource in the United States is the College Diabetes Network, a not-for-profit organization whose mission is to equip young adults with type 1 diabetes to successfully manage the challenging transition to independence at college and beyond.

“The sweetest thing that can happen to us as adult diabetes providers is when a patient – seen as an emerging adult during college – returns to your practice 10 years later after moving back and seeks you out for their diabetes care because of the relationship and trust you developed in those transitioning years,” Dr. Aleppo said.

Another resource is a freely available comic book series cocreated by Dr. Kar and colleague Mayank Patel, MBBS, an endocrinologist from University Hospital Southampton NHS Foundation Trust.

As detailed by this news organization in 2021, the series consists of three volumes: the first, Type 1: Origins, focuses on actual experiences of patients who have type 1 diabetes; the second, Type 1: Attack of the Ketones, is aimed at professionals who may provide care but have limited understanding of type 1 diabetes; and the third, Type 1 Mission 3: S.T.I.G.M.A., addresses the stigmas and misconceptions that patients with type 1 diabetes may face.

The idea for the first comic was inspired by a patient who compared having diabetes to being like the Marvel character The Hulk, said Dr. Kar, and has been expanded to include the additional volumes.

Dr. Kar and Dr. Patel have also just launched the fourth comic in the series, Type 1: Generations, to mark the 100-year anniversary since insulin was first given to a human.
 

“This is high priority”  

Dr. Kar said the NHS in England has just appointed a national lead for type 1 diabetes in youth, Fulya Mehta, MD, of Alder Hey Children’s NHS Foundation Trust, Liverpool, England.

“If you have a plan, bring it to us,” he told the audience at the DPC conference, and “tell us, what is the one thing you would change? This is not a session we are doing just to tick a box. This is high priority.

“Encourage your colleagues to think about transition services. This is an absolute priority. We will be asking every center [in England] who is your transitioning lead?”

And he once again stressed that “a lead of transition service does not have to be a medic. This should be a multidisciplinary team. But they do need to be comfortable in that space. To that teenager, your job title means nothing. Give them time and space.”

Dr. Randell summed it up: “If we can work together, it’s only going to result in better outcomes. We need to blaze the trail for young people.”

Dr. Aleppo has reported serving as a consultant to Dexcom and Insulet and receiving support to Northwestern University from AstraZeneca, Dexcom, Eli Lilly, Fractyl Health, Insulet, and Novo Nordisk. Dr. Randell and Dr. Kar have no conflicts of interest.

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

Evidence summary

Alone or in combination with hCG, clomiphene citrate is effective

A 2018 multicenter prospective RCT (n = 283) compared the serum testosterone response in men (mean age, 41.8 ± 10.4 years) with hypogonadism before and after treatment with either CC, human chorionic gonadotropin (hCG), or a combination of both therapies.¹ All patients wanted to maintain fertility, had normal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, had no history of testosterone therapy, had low (< 300 ng/dL) serum testosterone levels on at least 2 samples, and had at least 3 positive symptoms from the quantitative Androgen Deficiency in the Aging Male questionnaire (qADAM; a 10-item, graded-response tool measuring symptom severity from 1 to 5).

Patients were randomized into either the CC group (50 mg oral; n = 95), the hCG group (5000 IU injections twice weekly; n = 94), or the CC + hCG group (n = 94). Testosterone levels were measured at baseline and at 1 and 3 months after therapy initiation; qADAM questionnaire scores were also recorded but ultimately not used due to concerns with baseline heterogeneity among groups.

Average baseline serum testosterone levels for the CC, hCG, and CC + hCG groups were 243 ng/dL, 222 ng/dL, and 226 ng/dL, respectively. By 3 months, these levels had increased to 548 ng/dL (95% CI, 505-591) in the CC group, 467 ng/dL (95% CI, 440-494) in the hCG group, and 531 ng/dL (95% CI, 492-570) in the CC + hCG group. While there was not a significant difference between the CC and CC + hCG groups at 3 months (P = .579), both groups were superior to the hCG-only group (P = .002 for each).

CC and testosterone gel are comparable; testosterone injection is better

In a 2014 retrospective study, researchers reviewed the charts of 1150 men taking any form of testosterone supplementation therapy (TST). They compared treatment efficacy and qADAM satisfaction scores in 93 age-matched men with symptomatic hypogonadism who were treated with either CC (n = 31), testosterone injections (n = 31), or testosterone topical gel (n = 31).² Eugonadal men not taking TST (n = 31) served as controls.

Inclusion criteria were based on treatment regimens of CC and TST. Participants in the treatment groups had a baseline total testosterone level < 300 ng/dL and had reported ≤ 3 positive symptoms on the qADAM questionnaire. Treatment regimens included CC (25 mg orally once daily), testosterone injections (testosterone cypionate 100 to 200 mg intramuscularly once weekly), and testosterone gel (Testim 1% or AndroGel 1.62%, 2 to 4 pumps/d).

The study results demonstrated an increase in median testosterone from baseline levels in all treatment groups when compared to placebo: CC (from 247 to 504 ng/dL), testosterone injections (from 224 to 1104 ng/dL), and testosterone gels (from 230 to 412 ng/dL) (P < .05). Men receiving testosterone injections had the highest increase in serum testosterone levels (956 ng/dL).

While the final mean serum total testosterone was highest in the testosterone injection group (1014 ng/dL; P < .01), the mean levels for those using CC and those using testosterone gels were comparable (525 ng/dL vs 412 ng/dL). Serum estradiol levels were also higher in men receiving testosterone injections, compared to men using CC, those using testosterone gels, and those not receiving TST (6.0 vs 2.0, 2.0, and 2.0 ng/dL, respectively; each P < .01).

Continue to: The qADAM scores...

The qADAM scores for hypogonadal symptoms showed no significant difference in men treated with CC, testosterone injections, and testosterone gels and those not receiving TST (35, 39, 36, and 34, respectively). Men receiving testosterone injections reported greater libido (range, 1-5) than men using CC, those using testosterone gels, and those not on TST (4 vs 3, 3, and 3; P = .047, .04, and < .01, respectively), but it is uncertain if this is clinically meaningful.

Enclomiphene citrate demonstrates improvement in hormone levels

A 2014 Phase II RCT investigated the effects of oral EC—a trans-isomer of CC—compared to topical testosterone 1% gel (T gel) in 124 men with secondary hypogonadism.³ Entry criteria included a baseline morning total testosterone level of < 250 ng/dL on 2 occasions. Participants were divided into 4 groups: 12.5-mg dose of EC, 25-mg dose of EC, T gel, and placebo.

The EC groups and the T gel group had comparable increases in testosterone levels after 3 months of treatment, without statistical significance. The 3-month change in serum testosterone level from baseline was 217 to 471 ng/dL (95% CI, 399-543) in the 12.5-mg dose group; 209 to 405 ng/dL (95% CI, 349-462) in the 25-mg dose group; and 210 to 462 ng/dL (95% CI, 359-565) in the T gel group. The placebo group had a decrease in serum testosterone levels, from 213 to 198 ng/dL (95% CI, 171-226).

Men with low or low-normal serum luteinizing hormone levels may be good candidates for the use of SERMs for management of testosterone deficiency.

Also, the EC groups demonstrated increases in LH and FSH levels from baseline to 3 months, while the T gel group showed a suppression (to low-normal range) in both levels: LH, 1.4 mIU/mL (decrease of 4.4 mIU/mL) and FSH, 2.4 mIU/mL (decrease of 2.4 mIU/mL). Among a subset of men (n = 67) who had at least 2 assessments at the end of 3 months, the researchers also analyzed changes in sperm concentration, using the lower limit of normal (15 million/mL). The number of men with a low sperm concentration increased significantly in the topical T gel group (16% to 53%) compared to the 12.5-mg EC group (decrease from 16% to 12%; P = .0008) and the 25-mg EC group (decrease from 5% to 0%; P = .0007), as well as compared to the placebo group (increase from 8% to 15%; P = .007).

With EC, testosterone remains elevated after treatment cessation

A 2016 2-center parallel, double-blind, ­placebo-controlled RCT evaluated the effect of 2 doses of EC (12.5 mg and 25 mg; n = 85) vs testosterone gel (1.62%; n = 85) vs placebo (n = 86) on serum testosterone, LH, FSH, and sperm counts in 256 overweight and obese men ages 18 to 60 years who had 2 morning testosterone measurements < 300 ng/dL and a low or inappropriately normal LH level for 16 weeks.⁴ All baseline characteristics, including age, BMI, sperm concentration, and serum total testosterone were statistically consistent within groups at both centers. For men receiving EC who did not achieve a testosterone level > 450 ng/dL, there was an up-titration from 12.5 mg to 25 mg at Week 4.

Continue to: All active treatment groups...

All active treatment groups showed increases in testosterone level during treatment (P < .001); however, FSH and LH levels increased in the EC group and decreased in the testosterone gel group (P < .001). Serum testosterone levels improved to 428.8 ng/dL (95% CI, 395-462) and 368.8 ng/dL (95% CI, 307-431), respectively, in the combined EC and testosterone gel groups at 16 weeks. Of note, total testosterone levels after cessation of treatment (off-drug point) rapidly decreased below baseline in the testosterone gel group compared to the pooled EC group, which remained elevated above baseline for at least 7 days.

Composite end-point analysis was performed, with success considered if men achieved both testosterone in normal range (300-1040 ng/dL) and sperm concentrations ≥ 10 × 10⁶. The pooled data studies showed EC was more successful than testosterone gel in achieving both endpoints (63.5% vs 24.7%; P < .001). No difference in the incidence of treatment-related adverse effects between groups was noted.

There were no major adverse effects, even after 3+ years of treatment

A 2019 retrospective cohort study of 400 men treated for symptomatic hypogonadism with CC sought to determine if improvements in testosterone, hypogonadal symptoms, and adverse effects were similar for those treated for ≤ 3 years (n = 280) and those treated for > 3 years (n = 120).⁵ Outcomes included serum testosterone and estradiol levels, symptom improvement (by qADAM questionnaire), and adverse effects.

All participants had a baseline testosterone level < 300 ng/dL, and all participants received CC therapy. Men received 25 mg/d with titration to 50 mg/d when testosterone did not improve to ≥ 300 ng/dL after 4 weeks.

When comparing outcomes across the 2 groups, there were no significant differences. Serum testosterone levels improved to 579 ng/dL (95% CI, 554-605) and 542 ng/dL (95% CI, 504-580) in the ≤ 3 years and > 3 years groups, respectively. Meanwhile, 79% of men in the ≤ 3 years group reported symptom improvement (improvement in libido, erection, or 3 other of the 10 domains of the qADAM questionnaire), while 77% of those in the > 3 years group reported improvement (P = .60).

Continue to: Finally, the percentage of men reporting...

Finally, the percentage of men reporting adverse effects did not significantly differ between groups: 9% in the ≤ 3 years group and 8% in the > 3 years group (P = .85). The most common adverse effects reported in order of frequency were mood changes, blurred vision, breast tenderness, hypertension, hematocrit changes, and flushing. No major adverse events (eg, myocardial infarction, cerebrovascular accident, venous thromboembolism, suicidal behavior) were reported in any patients.

Both the American Urological Association and the Canadian Urological Association support the use of SERMs, especially in hypogonadal men who are interested in fertility preservation.

Of note, although measured estrogen levels at the end of treatment were similar for both groups (54.8 pg/mL in the ≤ 3 years group vs 54.6 pg/mL in the > 3 years group), 37% of patients treated for > 3 years did receive anastrozole treatment for hyperestrogenism compared to 15% in the ≤ 3 years group (P = .05). The authors caution, though, that due to only 20% of the cohort patients having data on pre- and post-treatment estradiol levels, the study was likely underpowered to detect true differences among subgroups.

Recommendations from others

Current American Urological Association and Canadian Urological Association Guidelines note that while greater study on nontraditional testosterone therapies is needed, both organizations support use of SERMs, especially in hypogonadal men who are interested in fertility preservation, as increases in endogenous serum testosterone production do not impact fertility potential, unlike exogenous hormonal replacement.^6,7 Additionally, men with low or low-normal serum LH levels may also be good candidates for the use of SERMs for management of testosterone deficiency.

Editor’s takeaway

Laboratory data (disease oriented) consistently shows that SERMs effectively increase testosterone levels to those comparable with testosterone gels. SERMs resulted in higher semen counts and maintained LH and FSH levels, but there were instances of hyperestrogenism. Data on longer-term benefits and adverse effects of both SERMs and testosterone supplementation are still needed.

Evidence summary

Alone or in combination with hCG, clomiphene citrate is effective

A 2018 multicenter prospective RCT (n = 283) compared the serum testosterone response in men (mean age, 41.8 ± 10.4 years) with hypogonadism before and after treatment with either CC, human chorionic gonadotropin (hCG), or a combination of both therapies.¹ All patients wanted to maintain fertility, had normal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, had no history of testosterone therapy, had low (< 300 ng/dL) serum testosterone levels on at least 2 samples, and had at least 3 positive symptoms from the quantitative Androgen Deficiency in the Aging Male questionnaire (qADAM; a 10-item, graded-response tool measuring symptom severity from 1 to 5).

Patients were randomized into either the CC group (50 mg oral; n = 95), the hCG group (5000 IU injections twice weekly; n = 94), or the CC + hCG group (n = 94). Testosterone levels were measured at baseline and at 1 and 3 months after therapy initiation; qADAM questionnaire scores were also recorded but ultimately not used due to concerns with baseline heterogeneity among groups.

Average baseline serum testosterone levels for the CC, hCG, and CC + hCG groups were 243 ng/dL, 222 ng/dL, and 226 ng/dL, respectively. By 3 months, these levels had increased to 548 ng/dL (95% CI, 505-591) in the CC group, 467 ng/dL (95% CI, 440-494) in the hCG group, and 531 ng/dL (95% CI, 492-570) in the CC + hCG group. While there was not a significant difference between the CC and CC + hCG groups at 3 months (P = .579), both groups were superior to the hCG-only group (P = .002 for each).

CC and testosterone gel are comparable; testosterone injection is better

In a 2014 retrospective study, researchers reviewed the charts of 1150 men taking any form of testosterone supplementation therapy (TST). They compared treatment efficacy and qADAM satisfaction scores in 93 age-matched men with symptomatic hypogonadism who were treated with either CC (n = 31), testosterone injections (n = 31), or testosterone topical gel (n = 31).² Eugonadal men not taking TST (n = 31) served as controls.

Inclusion criteria were based on treatment regimens of CC and TST. Participants in the treatment groups had a baseline total testosterone level < 300 ng/dL and had reported ≤ 3 positive symptoms on the qADAM questionnaire. Treatment regimens included CC (25 mg orally once daily), testosterone injections (testosterone cypionate 100 to 200 mg intramuscularly once weekly), and testosterone gel (Testim 1% or AndroGel 1.62%, 2 to 4 pumps/d).

The study results demonstrated an increase in median testosterone from baseline levels in all treatment groups when compared to placebo: CC (from 247 to 504 ng/dL), testosterone injections (from 224 to 1104 ng/dL), and testosterone gels (from 230 to 412 ng/dL) (P < .05). Men receiving testosterone injections had the highest increase in serum testosterone levels (956 ng/dL).

While the final mean serum total testosterone was highest in the testosterone injection group (1014 ng/dL; P < .01), the mean levels for those using CC and those using testosterone gels were comparable (525 ng/dL vs 412 ng/dL). Serum estradiol levels were also higher in men receiving testosterone injections, compared to men using CC, those using testosterone gels, and those not receiving TST (6.0 vs 2.0, 2.0, and 2.0 ng/dL, respectively; each P < .01).

Continue to: The qADAM scores...

The qADAM scores for hypogonadal symptoms showed no significant difference in men treated with CC, testosterone injections, and testosterone gels and those not receiving TST (35, 39, 36, and 34, respectively). Men receiving testosterone injections reported greater libido (range, 1-5) than men using CC, those using testosterone gels, and those not on TST (4 vs 3, 3, and 3; P = .047, .04, and < .01, respectively), but it is uncertain if this is clinically meaningful.

Enclomiphene citrate demonstrates improvement in hormone levels

A 2014 Phase II RCT investigated the effects of oral EC—a trans-isomer of CC—compared to topical testosterone 1% gel (T gel) in 124 men with secondary hypogonadism.³ Entry criteria included a baseline morning total testosterone level of < 250 ng/dL on 2 occasions. Participants were divided into 4 groups: 12.5-mg dose of EC, 25-mg dose of EC, T gel, and placebo.

The EC groups and the T gel group had comparable increases in testosterone levels after 3 months of treatment, without statistical significance. The 3-month change in serum testosterone level from baseline was 217 to 471 ng/dL (95% CI, 399-543) in the 12.5-mg dose group; 209 to 405 ng/dL (95% CI, 349-462) in the 25-mg dose group; and 210 to 462 ng/dL (95% CI, 359-565) in the T gel group. The placebo group had a decrease in serum testosterone levels, from 213 to 198 ng/dL (95% CI, 171-226).

Men with low or low-normal serum luteinizing hormone levels may be good candidates for the use of SERMs for management of testosterone deficiency.

Also, the EC groups demonstrated increases in LH and FSH levels from baseline to 3 months, while the T gel group showed a suppression (to low-normal range) in both levels: LH, 1.4 mIU/mL (decrease of 4.4 mIU/mL) and FSH, 2.4 mIU/mL (decrease of 2.4 mIU/mL). Among a subset of men (n = 67) who had at least 2 assessments at the end of 3 months, the researchers also analyzed changes in sperm concentration, using the lower limit of normal (15 million/mL). The number of men with a low sperm concentration increased significantly in the topical T gel group (16% to 53%) compared to the 12.5-mg EC group (decrease from 16% to 12%; P = .0008) and the 25-mg EC group (decrease from 5% to 0%; P = .0007), as well as compared to the placebo group (increase from 8% to 15%; P = .007).

With EC, testosterone remains elevated after treatment cessation

A 2016 2-center parallel, double-blind, ­placebo-controlled RCT evaluated the effect of 2 doses of EC (12.5 mg and 25 mg; n = 85) vs testosterone gel (1.62%; n = 85) vs placebo (n = 86) on serum testosterone, LH, FSH, and sperm counts in 256 overweight and obese men ages 18 to 60 years who had 2 morning testosterone measurements < 300 ng/dL and a low or inappropriately normal LH level for 16 weeks.⁴ All baseline characteristics, including age, BMI, sperm concentration, and serum total testosterone were statistically consistent within groups at both centers. For men receiving EC who did not achieve a testosterone level > 450 ng/dL, there was an up-titration from 12.5 mg to 25 mg at Week 4.

Continue to: All active treatment groups...

All active treatment groups showed increases in testosterone level during treatment (P < .001); however, FSH and LH levels increased in the EC group and decreased in the testosterone gel group (P < .001). Serum testosterone levels improved to 428.8 ng/dL (95% CI, 395-462) and 368.8 ng/dL (95% CI, 307-431), respectively, in the combined EC and testosterone gel groups at 16 weeks. Of note, total testosterone levels after cessation of treatment (off-drug point) rapidly decreased below baseline in the testosterone gel group compared to the pooled EC group, which remained elevated above baseline for at least 7 days.

Composite end-point analysis was performed, with success considered if men achieved both testosterone in normal range (300-1040 ng/dL) and sperm concentrations ≥ 10 × 10⁶. The pooled data studies showed EC was more successful than testosterone gel in achieving both endpoints (63.5% vs 24.7%; P < .001). No difference in the incidence of treatment-related adverse effects between groups was noted.

There were no major adverse effects, even after 3+ years of treatment

A 2019 retrospective cohort study of 400 men treated for symptomatic hypogonadism with CC sought to determine if improvements in testosterone, hypogonadal symptoms, and adverse effects were similar for those treated for ≤ 3 years (n = 280) and those treated for > 3 years (n = 120).⁵ Outcomes included serum testosterone and estradiol levels, symptom improvement (by qADAM questionnaire), and adverse effects.

All participants had a baseline testosterone level < 300 ng/dL, and all participants received CC therapy. Men received 25 mg/d with titration to 50 mg/d when testosterone did not improve to ≥ 300 ng/dL after 4 weeks.

When comparing outcomes across the 2 groups, there were no significant differences. Serum testosterone levels improved to 579 ng/dL (95% CI, 554-605) and 542 ng/dL (95% CI, 504-580) in the ≤ 3 years and > 3 years groups, respectively. Meanwhile, 79% of men in the ≤ 3 years group reported symptom improvement (improvement in libido, erection, or 3 other of the 10 domains of the qADAM questionnaire), while 77% of those in the > 3 years group reported improvement (P = .60).

Continue to: Finally, the percentage of men reporting...

Finally, the percentage of men reporting adverse effects did not significantly differ between groups: 9% in the ≤ 3 years group and 8% in the > 3 years group (P = .85). The most common adverse effects reported in order of frequency were mood changes, blurred vision, breast tenderness, hypertension, hematocrit changes, and flushing. No major adverse events (eg, myocardial infarction, cerebrovascular accident, venous thromboembolism, suicidal behavior) were reported in any patients.

Both the American Urological Association and the Canadian Urological Association support the use of SERMs, especially in hypogonadal men who are interested in fertility preservation.

Of note, although measured estrogen levels at the end of treatment were similar for both groups (54.8 pg/mL in the ≤ 3 years group vs 54.6 pg/mL in the > 3 years group), 37% of patients treated for > 3 years did receive anastrozole treatment for hyperestrogenism compared to 15% in the ≤ 3 years group (P = .05). The authors caution, though, that due to only 20% of the cohort patients having data on pre- and post-treatment estradiol levels, the study was likely underpowered to detect true differences among subgroups.

Recommendations from others

Current American Urological Association and Canadian Urological Association Guidelines note that while greater study on nontraditional testosterone therapies is needed, both organizations support use of SERMs, especially in hypogonadal men who are interested in fertility preservation, as increases in endogenous serum testosterone production do not impact fertility potential, unlike exogenous hormonal replacement.^6,7 Additionally, men with low or low-normal serum LH levels may also be good candidates for the use of SERMs for management of testosterone deficiency.

Editor’s takeaway

Laboratory data (disease oriented) consistently shows that SERMs effectively increase testosterone levels to those comparable with testosterone gels. SERMs resulted in higher semen counts and maintained LH and FSH levels, but there were instances of hyperestrogenism. Data on longer-term benefits and adverse effects of both SERMs and testosterone supplementation are still needed.

Evidence summary

Alone or in combination with hCG, clomiphene citrate is effective

A 2018 multicenter prospective RCT (n = 283) compared the serum testosterone response in men (mean age, 41.8 ± 10.4 years) with hypogonadism before and after treatment with either CC, human chorionic gonadotropin (hCG), or a combination of both therapies.¹ All patients wanted to maintain fertility, had normal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, had no history of testosterone therapy, had low (< 300 ng/dL) serum testosterone levels on at least 2 samples, and had at least 3 positive symptoms from the quantitative Androgen Deficiency in the Aging Male questionnaire (qADAM; a 10-item, graded-response tool measuring symptom severity from 1 to 5).

Patients were randomized into either the CC group (50 mg oral; n = 95), the hCG group (5000 IU injections twice weekly; n = 94), or the CC + hCG group (n = 94). Testosterone levels were measured at baseline and at 1 and 3 months after therapy initiation; qADAM questionnaire scores were also recorded but ultimately not used due to concerns with baseline heterogeneity among groups.

Average baseline serum testosterone levels for the CC, hCG, and CC + hCG groups were 243 ng/dL, 222 ng/dL, and 226 ng/dL, respectively. By 3 months, these levels had increased to 548 ng/dL (95% CI, 505-591) in the CC group, 467 ng/dL (95% CI, 440-494) in the hCG group, and 531 ng/dL (95% CI, 492-570) in the CC + hCG group. While there was not a significant difference between the CC and CC + hCG groups at 3 months (P = .579), both groups were superior to the hCG-only group (P = .002 for each).

CC and testosterone gel are comparable; testosterone injection is better

In a 2014 retrospective study, researchers reviewed the charts of 1150 men taking any form of testosterone supplementation therapy (TST). They compared treatment efficacy and qADAM satisfaction scores in 93 age-matched men with symptomatic hypogonadism who were treated with either CC (n = 31), testosterone injections (n = 31), or testosterone topical gel (n = 31).² Eugonadal men not taking TST (n = 31) served as controls.

Inclusion criteria were based on treatment regimens of CC and TST. Participants in the treatment groups had a baseline total testosterone level < 300 ng/dL and had reported ≤ 3 positive symptoms on the qADAM questionnaire. Treatment regimens included CC (25 mg orally once daily), testosterone injections (testosterone cypionate 100 to 200 mg intramuscularly once weekly), and testosterone gel (Testim 1% or AndroGel 1.62%, 2 to 4 pumps/d).

The study results demonstrated an increase in median testosterone from baseline levels in all treatment groups when compared to placebo: CC (from 247 to 504 ng/dL), testosterone injections (from 224 to 1104 ng/dL), and testosterone gels (from 230 to 412 ng/dL) (P < .05). Men receiving testosterone injections had the highest increase in serum testosterone levels (956 ng/dL).

While the final mean serum total testosterone was highest in the testosterone injection group (1014 ng/dL; P < .01), the mean levels for those using CC and those using testosterone gels were comparable (525 ng/dL vs 412 ng/dL). Serum estradiol levels were also higher in men receiving testosterone injections, compared to men using CC, those using testosterone gels, and those not receiving TST (6.0 vs 2.0, 2.0, and 2.0 ng/dL, respectively; each P < .01).

Continue to: The qADAM scores...

The qADAM scores for hypogonadal symptoms showed no significant difference in men treated with CC, testosterone injections, and testosterone gels and those not receiving TST (35, 39, 36, and 34, respectively). Men receiving testosterone injections reported greater libido (range, 1-5) than men using CC, those using testosterone gels, and those not on TST (4 vs 3, 3, and 3; P = .047, .04, and < .01, respectively), but it is uncertain if this is clinically meaningful.

Enclomiphene citrate demonstrates improvement in hormone levels

A 2014 Phase II RCT investigated the effects of oral EC—a trans-isomer of CC—compared to topical testosterone 1% gel (T gel) in 124 men with secondary hypogonadism.³ Entry criteria included a baseline morning total testosterone level of < 250 ng/dL on 2 occasions. Participants were divided into 4 groups: 12.5-mg dose of EC, 25-mg dose of EC, T gel, and placebo.

The EC groups and the T gel group had comparable increases in testosterone levels after 3 months of treatment, without statistical significance. The 3-month change in serum testosterone level from baseline was 217 to 471 ng/dL (95% CI, 399-543) in the 12.5-mg dose group; 209 to 405 ng/dL (95% CI, 349-462) in the 25-mg dose group; and 210 to 462 ng/dL (95% CI, 359-565) in the T gel group. The placebo group had a decrease in serum testosterone levels, from 213 to 198 ng/dL (95% CI, 171-226).

Men with low or low-normal serum luteinizing hormone levels may be good candidates for the use of SERMs for management of testosterone deficiency.

Also, the EC groups demonstrated increases in LH and FSH levels from baseline to 3 months, while the T gel group showed a suppression (to low-normal range) in both levels: LH, 1.4 mIU/mL (decrease of 4.4 mIU/mL) and FSH, 2.4 mIU/mL (decrease of 2.4 mIU/mL). Among a subset of men (n = 67) who had at least 2 assessments at the end of 3 months, the researchers also analyzed changes in sperm concentration, using the lower limit of normal (15 million/mL). The number of men with a low sperm concentration increased significantly in the topical T gel group (16% to 53%) compared to the 12.5-mg EC group (decrease from 16% to 12%; P = .0008) and the 25-mg EC group (decrease from 5% to 0%; P = .0007), as well as compared to the placebo group (increase from 8% to 15%; P = .007).

With EC, testosterone remains elevated after treatment cessation

A 2016 2-center parallel, double-blind, ­placebo-controlled RCT evaluated the effect of 2 doses of EC (12.5 mg and 25 mg; n = 85) vs testosterone gel (1.62%; n = 85) vs placebo (n = 86) on serum testosterone, LH, FSH, and sperm counts in 256 overweight and obese men ages 18 to 60 years who had 2 morning testosterone measurements < 300 ng/dL and a low or inappropriately normal LH level for 16 weeks.⁴ All baseline characteristics, including age, BMI, sperm concentration, and serum total testosterone were statistically consistent within groups at both centers. For men receiving EC who did not achieve a testosterone level > 450 ng/dL, there was an up-titration from 12.5 mg to 25 mg at Week 4.

Continue to: All active treatment groups...

All active treatment groups showed increases in testosterone level during treatment (P < .001); however, FSH and LH levels increased in the EC group and decreased in the testosterone gel group (P < .001). Serum testosterone levels improved to 428.8 ng/dL (95% CI, 395-462) and 368.8 ng/dL (95% CI, 307-431), respectively, in the combined EC and testosterone gel groups at 16 weeks. Of note, total testosterone levels after cessation of treatment (off-drug point) rapidly decreased below baseline in the testosterone gel group compared to the pooled EC group, which remained elevated above baseline for at least 7 days.

Composite end-point analysis was performed, with success considered if men achieved both testosterone in normal range (300-1040 ng/dL) and sperm concentrations ≥ 10 × 10⁶. The pooled data studies showed EC was more successful than testosterone gel in achieving both endpoints (63.5% vs 24.7%; P < .001). No difference in the incidence of treatment-related adverse effects between groups was noted.

There were no major adverse effects, even after 3+ years of treatment

A 2019 retrospective cohort study of 400 men treated for symptomatic hypogonadism with CC sought to determine if improvements in testosterone, hypogonadal symptoms, and adverse effects were similar for those treated for ≤ 3 years (n = 280) and those treated for > 3 years (n = 120).⁵ Outcomes included serum testosterone and estradiol levels, symptom improvement (by qADAM questionnaire), and adverse effects.

All participants had a baseline testosterone level < 300 ng/dL, and all participants received CC therapy. Men received 25 mg/d with titration to 50 mg/d when testosterone did not improve to ≥ 300 ng/dL after 4 weeks.

When comparing outcomes across the 2 groups, there were no significant differences. Serum testosterone levels improved to 579 ng/dL (95% CI, 554-605) and 542 ng/dL (95% CI, 504-580) in the ≤ 3 years and > 3 years groups, respectively. Meanwhile, 79% of men in the ≤ 3 years group reported symptom improvement (improvement in libido, erection, or 3 other of the 10 domains of the qADAM questionnaire), while 77% of those in the > 3 years group reported improvement (P = .60).

Continue to: Finally, the percentage of men reporting...

Finally, the percentage of men reporting adverse effects did not significantly differ between groups: 9% in the ≤ 3 years group and 8% in the > 3 years group (P = .85). The most common adverse effects reported in order of frequency were mood changes, blurred vision, breast tenderness, hypertension, hematocrit changes, and flushing. No major adverse events (eg, myocardial infarction, cerebrovascular accident, venous thromboembolism, suicidal behavior) were reported in any patients.

Both the American Urological Association and the Canadian Urological Association support the use of SERMs, especially in hypogonadal men who are interested in fertility preservation.

Of note, although measured estrogen levels at the end of treatment were similar for both groups (54.8 pg/mL in the ≤ 3 years group vs 54.6 pg/mL in the > 3 years group), 37% of patients treated for > 3 years did receive anastrozole treatment for hyperestrogenism compared to 15% in the ≤ 3 years group (P = .05). The authors caution, though, that due to only 20% of the cohort patients having data on pre- and post-treatment estradiol levels, the study was likely underpowered to detect true differences among subgroups.

Recommendations from others

Current American Urological Association and Canadian Urological Association Guidelines note that while greater study on nontraditional testosterone therapies is needed, both organizations support use of SERMs, especially in hypogonadal men who are interested in fertility preservation, as increases in endogenous serum testosterone production do not impact fertility potential, unlike exogenous hormonal replacement.^6,7 Additionally, men with low or low-normal serum LH levels may also be good candidates for the use of SERMs for management of testosterone deficiency.

Editor’s takeaway

Laboratory data (disease oriented) consistently shows that SERMs effectively increase testosterone levels to those comparable with testosterone gels. SERMs resulted in higher semen counts and maintained LH and FSH levels, but there were instances of hyperestrogenism. Data on longer-term benefits and adverse effects of both SERMs and testosterone supplementation are still needed.

Pregnant women’s thyroid hormone trajectories (levels in the first, second, and third trimester) may predict whether their male offspring are aggressive or withdrawn at age 4.

Certain maternal thyroid hormone trajectories were associated with problem behaviors in preschool boys in a study of close to 2,000 mother-child pairs in China.

The researchers identified low, moderate, and high thyroid-stimulating hormone (TSH) and free thyroxine (FT4) trajectories. 

shironosov/Getty Images

‘Study supports monitoring thyroid function in pregnancy’

“Our findings highlight the significance of close monitoring and management of maternal thyroid function during pregnancy,” senior author Kun Huang, PhD, said in a press release from the Endocrine Society.

“This research presents a new perspective in early intervention of children’s emotional and behavioral problems,” added Dr. Huang, from Anhui Medical University, Hefei, China.

The results add to a growing body of literature about a controversial link between maternal thyroid hormones in pregnancy, when the fetal brain is developing, and subsequent behavior in preschool children, Caroline T. Nguyen, MD, who was not involved with this research, commented in an email.

“Some studies show an association between thyroid levels and behavioral outcomes, others not,” added Dr. Nguyen, assistant professor of clinical medicine, Keck School of Medicine, University of Southern California, Los Angeles. And “some studies have found sex-specific associations with maternal thyroid levels and neurocognitive/behavioral outcomes, others have not.”

Women considering pregnancy should be evaluated for possible thyroid disease, she continued. Currently, no universal screening mandates exist for thyroid disease in pregnancy, but the 2017 American Thyroid Association guidelines do recommend screening women at risk for thyroid dysfunction.

“I think screening for thyroid peroxidase antibody (TPOAb) positivity is helpful in women desiring pregnancy,” Dr. Nguyen continued, “because we know that patients with TPOAb positivity are at increased risk for miscarriage and have a blunted response to the increased demands of pregnancy for thyroid hormone production.”

TPOAb positivity is also associated with the increased risk of postpartum and long-term thyroid dysfunction.

This current study, Dr. Nguyen summarized, “adds to a growing body of research of the relationship of thyroid hormone levels and neurocognitive outcomes [in offspring] and supports the monitoring of thyroid disease in pregnancy.”  

“However, we do not have sufficient data to demonstrate the benefits of intervention with levothyroxine treatment,” she noted. 

Nevertheless, the lack of positive data does not suggest there is no theoretical benefit of intervention, she said, as such studies are very challenging to do. 

“Physicians can help reduce stress and anxiety in patients desiring pregnancy by [recommending] preconception counseling, screening patients at risk for thyroid disease, and optimizing thyroid hormone levels before and during pregnancy,” according to Dr. Nguyen.
 

Maternal TSH and FT4 trajectories and preschoolers’ behaviors

Previous studies have reported that during pregnancy, maternal subclinical hypothyroidism (elevated TSH with normal FT4) as well as isolated hypothyroxinemia (decreased FT4 with normal TSH) are associated with adverse maternal and child outcomes, including preterm delivery and low birth weight.

However, most studies have not determined maternal thyroid hormone levels in different trimesters.

Researchers recruited pregnant women going for their first antenatal checkup at the Ma’anshan Maternal and Child Health Hospital in China from May 2013 to September 2014 and identified 1,860 mother-child pairs.

They determined maternal thyroid hormone levels from blood samples taken during the first, second, and third trimester: on average, gestational week 10, 25, and 34, respectively.

The researchers found that TSH levels increased somewhat from trimester 1 to trimester 2 and then decreased slightly in trimester 3. Most women (68%) had a low TSH trajectory, 28% had a moderate TSH trajectory, and 4% had a high TSH trajectory.

FT4 levels dropped sharply from trimester 1 to trimester 2 and then increased somewhat in trimester 3. About half of the women (52%) had a moderate FT4 trajectory, 33% had a low FT4 trajectory, and 15% had a high FT4 trajectory.

Most women (96.5%) had a low and stable TPOAb level, and the rest (3.5%) had high and decreasing TPOAb levels.  

When the children in the study were 4 years old, their main caregiver (parent or grandparent) completed the 100-question Achenbach Child Behavior checklist to identify whether the child often, sometimes, or never displayed three internalizing problem behaviors (emotionally reactive, anxious/depressed, or withdrawn) and/or two externalizing problem behaviors (attention problems or aggressive behavior).
 

Study limitations, more research needed

It is not clear why the associations between maternal hormones and offspring behavior were only seen in boys. Perhaps male fetuses are more sensitive than female fetuses to changing maternal thyroid hormone levels in pregnancy, the researchers speculate.

They acknowledge that study limitations include there were few children with aggressive behavior, so the confidence interval for the association of the moderate TSH trajectory with aggressive behavior was very wide.

In addition, evaluation of children’s behavior by caregivers was subjective. Also, the researchers did not have information about iodine levels, and low iodine levels can impair child brain development.

And there may have been residual confounders that researchers did not account for, such as differences in family upbringing, parental marital status, and the mother’s exposure to endocrine disruptors.

Therefore, further research is needed.

The study was supported by grants from the National Natural Science Foundation of China, the University Synergy Innovation Program of Anhui Province, the Sci-Tech Basic Resources Research Program of China, the National Key Research and Development Program, the Chinese Academy of Medical Sciences, and the Research Fund of Anhui Institute of Translational Medicine. The researchers and Dr. Nguyen have reported no relevant financial relationships.

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

Pregnant women’s thyroid hormone trajectories (levels in the first, second, and third trimester) may predict whether their male offspring are aggressive or withdrawn at age 4.

Certain maternal thyroid hormone trajectories were associated with problem behaviors in preschool boys in a study of close to 2,000 mother-child pairs in China.

The researchers identified low, moderate, and high thyroid-stimulating hormone (TSH) and free thyroxine (FT4) trajectories. 

shironosov/Getty Images

‘Study supports monitoring thyroid function in pregnancy’

“Our findings highlight the significance of close monitoring and management of maternal thyroid function during pregnancy,” senior author Kun Huang, PhD, said in a press release from the Endocrine Society.

“This research presents a new perspective in early intervention of children’s emotional and behavioral problems,” added Dr. Huang, from Anhui Medical University, Hefei, China.

The results add to a growing body of literature about a controversial link between maternal thyroid hormones in pregnancy, when the fetal brain is developing, and subsequent behavior in preschool children, Caroline T. Nguyen, MD, who was not involved with this research, commented in an email.

“Some studies show an association between thyroid levels and behavioral outcomes, others not,” added Dr. Nguyen, assistant professor of clinical medicine, Keck School of Medicine, University of Southern California, Los Angeles. And “some studies have found sex-specific associations with maternal thyroid levels and neurocognitive/behavioral outcomes, others have not.”

Women considering pregnancy should be evaluated for possible thyroid disease, she continued. Currently, no universal screening mandates exist for thyroid disease in pregnancy, but the 2017 American Thyroid Association guidelines do recommend screening women at risk for thyroid dysfunction.

“I think screening for thyroid peroxidase antibody (TPOAb) positivity is helpful in women desiring pregnancy,” Dr. Nguyen continued, “because we know that patients with TPOAb positivity are at increased risk for miscarriage and have a blunted response to the increased demands of pregnancy for thyroid hormone production.”

TPOAb positivity is also associated with the increased risk of postpartum and long-term thyroid dysfunction.

This current study, Dr. Nguyen summarized, “adds to a growing body of research of the relationship of thyroid hormone levels and neurocognitive outcomes [in offspring] and supports the monitoring of thyroid disease in pregnancy.”  

“However, we do not have sufficient data to demonstrate the benefits of intervention with levothyroxine treatment,” she noted. 

Nevertheless, the lack of positive data does not suggest there is no theoretical benefit of intervention, she said, as such studies are very challenging to do. 

“Physicians can help reduce stress and anxiety in patients desiring pregnancy by [recommending] preconception counseling, screening patients at risk for thyroid disease, and optimizing thyroid hormone levels before and during pregnancy,” according to Dr. Nguyen.
 

Maternal TSH and FT4 trajectories and preschoolers’ behaviors

Previous studies have reported that during pregnancy, maternal subclinical hypothyroidism (elevated TSH with normal FT4) as well as isolated hypothyroxinemia (decreased FT4 with normal TSH) are associated with adverse maternal and child outcomes, including preterm delivery and low birth weight.

However, most studies have not determined maternal thyroid hormone levels in different trimesters.

Researchers recruited pregnant women going for their first antenatal checkup at the Ma’anshan Maternal and Child Health Hospital in China from May 2013 to September 2014 and identified 1,860 mother-child pairs.

They determined maternal thyroid hormone levels from blood samples taken during the first, second, and third trimester: on average, gestational week 10, 25, and 34, respectively.

The researchers found that TSH levels increased somewhat from trimester 1 to trimester 2 and then decreased slightly in trimester 3. Most women (68%) had a low TSH trajectory, 28% had a moderate TSH trajectory, and 4% had a high TSH trajectory.

FT4 levels dropped sharply from trimester 1 to trimester 2 and then increased somewhat in trimester 3. About half of the women (52%) had a moderate FT4 trajectory, 33% had a low FT4 trajectory, and 15% had a high FT4 trajectory.

Most women (96.5%) had a low and stable TPOAb level, and the rest (3.5%) had high and decreasing TPOAb levels.  

When the children in the study were 4 years old, their main caregiver (parent or grandparent) completed the 100-question Achenbach Child Behavior checklist to identify whether the child often, sometimes, or never displayed three internalizing problem behaviors (emotionally reactive, anxious/depressed, or withdrawn) and/or two externalizing problem behaviors (attention problems or aggressive behavior).
 

Study limitations, more research needed

It is not clear why the associations between maternal hormones and offspring behavior were only seen in boys. Perhaps male fetuses are more sensitive than female fetuses to changing maternal thyroid hormone levels in pregnancy, the researchers speculate.

They acknowledge that study limitations include there were few children with aggressive behavior, so the confidence interval for the association of the moderate TSH trajectory with aggressive behavior was very wide.

In addition, evaluation of children’s behavior by caregivers was subjective. Also, the researchers did not have information about iodine levels, and low iodine levels can impair child brain development.

And there may have been residual confounders that researchers did not account for, such as differences in family upbringing, parental marital status, and the mother’s exposure to endocrine disruptors.

Therefore, further research is needed.

The study was supported by grants from the National Natural Science Foundation of China, the University Synergy Innovation Program of Anhui Province, the Sci-Tech Basic Resources Research Program of China, the National Key Research and Development Program, the Chinese Academy of Medical Sciences, and the Research Fund of Anhui Institute of Translational Medicine. The researchers and Dr. Nguyen have reported no relevant financial relationships.

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

Pregnant women’s thyroid hormone trajectories (levels in the first, second, and third trimester) may predict whether their male offspring are aggressive or withdrawn at age 4.

Certain maternal thyroid hormone trajectories were associated with problem behaviors in preschool boys in a study of close to 2,000 mother-child pairs in China.

The researchers identified low, moderate, and high thyroid-stimulating hormone (TSH) and free thyroxine (FT4) trajectories. 

shironosov/Getty Images

‘Study supports monitoring thyroid function in pregnancy’

“Our findings highlight the significance of close monitoring and management of maternal thyroid function during pregnancy,” senior author Kun Huang, PhD, said in a press release from the Endocrine Society.

“This research presents a new perspective in early intervention of children’s emotional and behavioral problems,” added Dr. Huang, from Anhui Medical University, Hefei, China.

The results add to a growing body of literature about a controversial link between maternal thyroid hormones in pregnancy, when the fetal brain is developing, and subsequent behavior in preschool children, Caroline T. Nguyen, MD, who was not involved with this research, commented in an email.

“Some studies show an association between thyroid levels and behavioral outcomes, others not,” added Dr. Nguyen, assistant professor of clinical medicine, Keck School of Medicine, University of Southern California, Los Angeles. And “some studies have found sex-specific associations with maternal thyroid levels and neurocognitive/behavioral outcomes, others have not.”

Women considering pregnancy should be evaluated for possible thyroid disease, she continued. Currently, no universal screening mandates exist for thyroid disease in pregnancy, but the 2017 American Thyroid Association guidelines do recommend screening women at risk for thyroid dysfunction.

“I think screening for thyroid peroxidase antibody (TPOAb) positivity is helpful in women desiring pregnancy,” Dr. Nguyen continued, “because we know that patients with TPOAb positivity are at increased risk for miscarriage and have a blunted response to the increased demands of pregnancy for thyroid hormone production.”

TPOAb positivity is also associated with the increased risk of postpartum and long-term thyroid dysfunction.

This current study, Dr. Nguyen summarized, “adds to a growing body of research of the relationship of thyroid hormone levels and neurocognitive outcomes [in offspring] and supports the monitoring of thyroid disease in pregnancy.”  

“However, we do not have sufficient data to demonstrate the benefits of intervention with levothyroxine treatment,” she noted. 

Nevertheless, the lack of positive data does not suggest there is no theoretical benefit of intervention, she said, as such studies are very challenging to do. 

“Physicians can help reduce stress and anxiety in patients desiring pregnancy by [recommending] preconception counseling, screening patients at risk for thyroid disease, and optimizing thyroid hormone levels before and during pregnancy,” according to Dr. Nguyen.
 

Maternal TSH and FT4 trajectories and preschoolers’ behaviors

Previous studies have reported that during pregnancy, maternal subclinical hypothyroidism (elevated TSH with normal FT4) as well as isolated hypothyroxinemia (decreased FT4 with normal TSH) are associated with adverse maternal and child outcomes, including preterm delivery and low birth weight.

However, most studies have not determined maternal thyroid hormone levels in different trimesters.

Researchers recruited pregnant women going for their first antenatal checkup at the Ma’anshan Maternal and Child Health Hospital in China from May 2013 to September 2014 and identified 1,860 mother-child pairs.

They determined maternal thyroid hormone levels from blood samples taken during the first, second, and third trimester: on average, gestational week 10, 25, and 34, respectively.

The researchers found that TSH levels increased somewhat from trimester 1 to trimester 2 and then decreased slightly in trimester 3. Most women (68%) had a low TSH trajectory, 28% had a moderate TSH trajectory, and 4% had a high TSH trajectory.

FT4 levels dropped sharply from trimester 1 to trimester 2 and then increased somewhat in trimester 3. About half of the women (52%) had a moderate FT4 trajectory, 33% had a low FT4 trajectory, and 15% had a high FT4 trajectory.

Most women (96.5%) had a low and stable TPOAb level, and the rest (3.5%) had high and decreasing TPOAb levels.  

When the children in the study were 4 years old, their main caregiver (parent or grandparent) completed the 100-question Achenbach Child Behavior checklist to identify whether the child often, sometimes, or never displayed three internalizing problem behaviors (emotionally reactive, anxious/depressed, or withdrawn) and/or two externalizing problem behaviors (attention problems or aggressive behavior).
 

Study limitations, more research needed

It is not clear why the associations between maternal hormones and offspring behavior were only seen in boys. Perhaps male fetuses are more sensitive than female fetuses to changing maternal thyroid hormone levels in pregnancy, the researchers speculate.

They acknowledge that study limitations include there were few children with aggressive behavior, so the confidence interval for the association of the moderate TSH trajectory with aggressive behavior was very wide.

In addition, evaluation of children’s behavior by caregivers was subjective. Also, the researchers did not have information about iodine levels, and low iodine levels can impair child brain development.

And there may have been residual confounders that researchers did not account for, such as differences in family upbringing, parental marital status, and the mother’s exposure to endocrine disruptors.

Therefore, further research is needed.

The study was supported by grants from the National Natural Science Foundation of China, the University Synergy Innovation Program of Anhui Province, the Sci-Tech Basic Resources Research Program of China, the National Key Research and Development Program, the Chinese Academy of Medical Sciences, and the Research Fund of Anhui Institute of Translational Medicine. The researchers and Dr. Nguyen have reported no relevant financial relationships.

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

Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.   

The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.

These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.

The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.

“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.

“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting. 

“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.

Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.

“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
 

Hip fracture risk with risedronate vs. alendronate drug holiday

Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.

Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.

Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.

They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.

Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.

Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.

Most of the patients were women (82%) and were White.

They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.

During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.

This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).  

The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).

However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34). 

There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).

The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.

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

Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.   

The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.

These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.

The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.

“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.

“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting. 

“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.

Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.

“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
 

Hip fracture risk with risedronate vs. alendronate drug holiday

Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.

Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.

Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.

They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.

Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.

Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.

Most of the patients were women (82%) and were White.

They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.

During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.

This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).  

The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).

However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34). 

There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).

The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.

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

Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.   

The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.

These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.

The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.

“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.

“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting. 

“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.

Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.

“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
 

Hip fracture risk with risedronate vs. alendronate drug holiday

Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.

Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.

Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.

They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.

Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.

Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.

Most of the patients were women (82%) and were White.

They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.

During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.

This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).  

The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).

However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34). 

There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).

The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.

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

A new document from the American Heart Association summarizes the latest research on cardiovascular risk factor management in type 2 diabetes, including medications, lifestyle, and social determinants of health.

Despite the availability of effective therapies for improving cardiovascular risk, in the United States fewer than one in five people with type 2 diabetes and without known cardiovascular disease meet control targets for a combination of A1c, blood pressure, LDL cholesterol, and nonsmoking status.

Volkan Ünalan/Thinkstock

That proportion drops to less than 1 in 10 if body mass index less than 30 kg/m² is included among the targets, and even less than that among individuals with established atherosclerotic cardiovascular disease, Joshua J. Joseph, MD, and colleagues point out in their paper, published online Jan. 10 in Circulation.

“This new scientific statement is an urgent call to action to follow the latest evidence-based approaches and to develop new best practices to advance type 2 diabetes treatment and care and reduce cardiovascular disease risk,” wrote Dr. Joseph, assistant professor of medicine in the division of endocrinology, diabetes, and metabolism at The Ohio State University, Columbus, Ohio, and coauthors.

The statement is not a guideline but an expert analysis that may inform future clinical practice guidelines, according to a press release from the AHA.

The new statement reviews evidence through June 2020 for lifestyle management of diabetes and weight, glycemic targets and control, blood pressure management, lipid management, antithrombotic therapy, and screening for cardiovascular and renal complications, including imaging. It also discusses the clinical implications of recent cardiovascular outcomes trials of newer glucose-lowering medications.

However, Dr. Joseph and colleagues point out, clinical care and treatment account for just 10%-20% of modifiable contributors to health outcomes. The other 80%-90% relate to social determinants of health, including health-related behaviors, socioeconomic factors, environmental factors, and racism.

“If we are to continue to advance the management of cardiovascular risk factors, we must also address the [social determinants of health] in the delivery of health care,” they noted.

Overall, they advise a patient-centered approach, meaning “reframing our clinical encounters to think about patients as people who live in families, communities, and societies that must be considered in their cardiovascular risk management.”

“People with [type 2 diabetes] face numerous barriers to health including access to care and equitable care, which must be considered when developing individualized care plans with our patients,” Dr. Joseph said in the AHA press release.
 

Lifestyle, medications for lowering A1c, BP, lipids

For lifestyle management, the authors say, “culturally appropriate recommendations through diabetes self-management education and support and medical nutrition therapy are key to meeting individualized goals for behavioral change and diabetes self-management.”

The document summarizes recommendations from other professional societies regarding glycemic targets and glucose lowering medications, i.e., target A1c levels of either < 7% or < 6.5% for the majority, with adjustments based on individual factors, such as life expectancy. It advises on use of metformin as first-line therapy followed by a sodium-glucose cotransporter-2 inhibitor or a glucagon-like peptide-1 agonist for those with established cardiovascular disease or risk factors.

“Cost may be a barrier to taking some [type 2 diabetes] medications as prescribed; however, many of these medications are now more commonly covered by more health insurance plans,” Dr. Joseph said.

“Another barrier is recognition by patients that these newer [type 2 diabetes] medications are also effective in reducing the risk of heart disease, stroke, heart failure, and kidney disease.”

Blood pressure treatment guidelines differ between those of the AHA/American College of Cardiology (ACC) and the American Diabetes Association (ADA), most notably that the AHA/ACC guidelines advise a general target of < 130/80 mm Hg, whereas ADA advises < 140/90 mm Hg or < 130/80 mm Hg for those with high risk if it can be safely achieved.

The decision should be “patient-centered with shared decision-making,” Dr. Joseph and colleagues advised.

For lipid-lowering, the document cites the 2018 ACC/AHA cholesterol guidelines, which include advising statins as first-line therapy for both primary and secondary prevention in diabetes, with highest intensity statins used in those at highest risk. But again, treatment should be individualized, and other agents should be used for patients in whom statins don’t work or aren’t tolerated.

And while use of antiplatelets – that is, aspirin – is well established as secondary prevention in type 2 diabetes, given new data suggesting that the risk for major bleeding could outweigh the benefits for primary prevention, “the relative benefits of antithrombotic approaches need to be weighed carefully against risks using a patient-centered approach,” the authors advised.

Among the many imaging tests available to facilitate cardiovascular risk stratification in type 2 diabetes, coronary artery calcification (CAC) CT screening is one of the few with sufficient data to support routine use in selected patients. The National Lipid Association, for example, recommends escalation to high-intensity statin for CAC > 100.

“One avenue to continue to address and advance diabetes management is through breaking down the four walls of the clinic or hospital through community engagement, clinic-to-community connections, and academic-community-government partnerships that may help address and support modifiable lifestyle behaviors such as physical activity, nutrition, smoking cessation and stress management,” Dr. Joseph concluded.

The AHA receives funding primarily from individuals. Foundations and corporations, including pharmaceutical, device manufacturers, and other companies, also make donations and fund AHA programs and events. The AHA’s strict policies prevent these relationships from influencing the science content. Revenues from pharmaceutical and biotech companies, device manufacturers, and health insurance providers and the AHA’s financial information are available on the association’s website. Dr. Joseph has disclosed no relevant financial relationships.

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

A new document from the American Heart Association summarizes the latest research on cardiovascular risk factor management in type 2 diabetes, including medications, lifestyle, and social determinants of health.

Despite the availability of effective therapies for improving cardiovascular risk, in the United States fewer than one in five people with type 2 diabetes and without known cardiovascular disease meet control targets for a combination of A1c, blood pressure, LDL cholesterol, and nonsmoking status.

Volkan Ünalan/Thinkstock

That proportion drops to less than 1 in 10 if body mass index less than 30 kg/m² is included among the targets, and even less than that among individuals with established atherosclerotic cardiovascular disease, Joshua J. Joseph, MD, and colleagues point out in their paper, published online Jan. 10 in Circulation.

“This new scientific statement is an urgent call to action to follow the latest evidence-based approaches and to develop new best practices to advance type 2 diabetes treatment and care and reduce cardiovascular disease risk,” wrote Dr. Joseph, assistant professor of medicine in the division of endocrinology, diabetes, and metabolism at The Ohio State University, Columbus, Ohio, and coauthors.

The statement is not a guideline but an expert analysis that may inform future clinical practice guidelines, according to a press release from the AHA.

The new statement reviews evidence through June 2020 for lifestyle management of diabetes and weight, glycemic targets and control, blood pressure management, lipid management, antithrombotic therapy, and screening for cardiovascular and renal complications, including imaging. It also discusses the clinical implications of recent cardiovascular outcomes trials of newer glucose-lowering medications.

However, Dr. Joseph and colleagues point out, clinical care and treatment account for just 10%-20% of modifiable contributors to health outcomes. The other 80%-90% relate to social determinants of health, including health-related behaviors, socioeconomic factors, environmental factors, and racism.

“If we are to continue to advance the management of cardiovascular risk factors, we must also address the [social determinants of health] in the delivery of health care,” they noted.

Overall, they advise a patient-centered approach, meaning “reframing our clinical encounters to think about patients as people who live in families, communities, and societies that must be considered in their cardiovascular risk management.”

“People with [type 2 diabetes] face numerous barriers to health including access to care and equitable care, which must be considered when developing individualized care plans with our patients,” Dr. Joseph said in the AHA press release.
 

Lifestyle, medications for lowering A1c, BP, lipids

For lifestyle management, the authors say, “culturally appropriate recommendations through diabetes self-management education and support and medical nutrition therapy are key to meeting individualized goals for behavioral change and diabetes self-management.”

The document summarizes recommendations from other professional societies regarding glycemic targets and glucose lowering medications, i.e., target A1c levels of either < 7% or < 6.5% for the majority, with adjustments based on individual factors, such as life expectancy. It advises on use of metformin as first-line therapy followed by a sodium-glucose cotransporter-2 inhibitor or a glucagon-like peptide-1 agonist for those with established cardiovascular disease or risk factors.

“Cost may be a barrier to taking some [type 2 diabetes] medications as prescribed; however, many of these medications are now more commonly covered by more health insurance plans,” Dr. Joseph said.

“Another barrier is recognition by patients that these newer [type 2 diabetes] medications are also effective in reducing the risk of heart disease, stroke, heart failure, and kidney disease.”

Blood pressure treatment guidelines differ between those of the AHA/American College of Cardiology (ACC) and the American Diabetes Association (ADA), most notably that the AHA/ACC guidelines advise a general target of < 130/80 mm Hg, whereas ADA advises < 140/90 mm Hg or < 130/80 mm Hg for those with high risk if it can be safely achieved.

The decision should be “patient-centered with shared decision-making,” Dr. Joseph and colleagues advised.

For lipid-lowering, the document cites the 2018 ACC/AHA cholesterol guidelines, which include advising statins as first-line therapy for both primary and secondary prevention in diabetes, with highest intensity statins used in those at highest risk. But again, treatment should be individualized, and other agents should be used for patients in whom statins don’t work or aren’t tolerated.

And while use of antiplatelets – that is, aspirin – is well established as secondary prevention in type 2 diabetes, given new data suggesting that the risk for major bleeding could outweigh the benefits for primary prevention, “the relative benefits of antithrombotic approaches need to be weighed carefully against risks using a patient-centered approach,” the authors advised.

Among the many imaging tests available to facilitate cardiovascular risk stratification in type 2 diabetes, coronary artery calcification (CAC) CT screening is one of the few with sufficient data to support routine use in selected patients. The National Lipid Association, for example, recommends escalation to high-intensity statin for CAC > 100.

“One avenue to continue to address and advance diabetes management is through breaking down the four walls of the clinic or hospital through community engagement, clinic-to-community connections, and academic-community-government partnerships that may help address and support modifiable lifestyle behaviors such as physical activity, nutrition, smoking cessation and stress management,” Dr. Joseph concluded.

The AHA receives funding primarily from individuals. Foundations and corporations, including pharmaceutical, device manufacturers, and other companies, also make donations and fund AHA programs and events. The AHA’s strict policies prevent these relationships from influencing the science content. Revenues from pharmaceutical and biotech companies, device manufacturers, and health insurance providers and the AHA’s financial information are available on the association’s website. Dr. Joseph has disclosed no relevant financial relationships.

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

A new document from the American Heart Association summarizes the latest research on cardiovascular risk factor management in type 2 diabetes, including medications, lifestyle, and social determinants of health.

Despite the availability of effective therapies for improving cardiovascular risk, in the United States fewer than one in five people with type 2 diabetes and without known cardiovascular disease meet control targets for a combination of A1c, blood pressure, LDL cholesterol, and nonsmoking status.

Volkan Ünalan/Thinkstock

That proportion drops to less than 1 in 10 if body mass index less than 30 kg/m² is included among the targets, and even less than that among individuals with established atherosclerotic cardiovascular disease, Joshua J. Joseph, MD, and colleagues point out in their paper, published online Jan. 10 in Circulation.

“This new scientific statement is an urgent call to action to follow the latest evidence-based approaches and to develop new best practices to advance type 2 diabetes treatment and care and reduce cardiovascular disease risk,” wrote Dr. Joseph, assistant professor of medicine in the division of endocrinology, diabetes, and metabolism at The Ohio State University, Columbus, Ohio, and coauthors.

The statement is not a guideline but an expert analysis that may inform future clinical practice guidelines, according to a press release from the AHA.

The new statement reviews evidence through June 2020 for lifestyle management of diabetes and weight, glycemic targets and control, blood pressure management, lipid management, antithrombotic therapy, and screening for cardiovascular and renal complications, including imaging. It also discusses the clinical implications of recent cardiovascular outcomes trials of newer glucose-lowering medications.

However, Dr. Joseph and colleagues point out, clinical care and treatment account for just 10%-20% of modifiable contributors to health outcomes. The other 80%-90% relate to social determinants of health, including health-related behaviors, socioeconomic factors, environmental factors, and racism.

“If we are to continue to advance the management of cardiovascular risk factors, we must also address the [social determinants of health] in the delivery of health care,” they noted.

Overall, they advise a patient-centered approach, meaning “reframing our clinical encounters to think about patients as people who live in families, communities, and societies that must be considered in their cardiovascular risk management.”

“People with [type 2 diabetes] face numerous barriers to health including access to care and equitable care, which must be considered when developing individualized care plans with our patients,” Dr. Joseph said in the AHA press release.
 

Lifestyle, medications for lowering A1c, BP, lipids

For lifestyle management, the authors say, “culturally appropriate recommendations through diabetes self-management education and support and medical nutrition therapy are key to meeting individualized goals for behavioral change and diabetes self-management.”

The document summarizes recommendations from other professional societies regarding glycemic targets and glucose lowering medications, i.e., target A1c levels of either < 7% or < 6.5% for the majority, with adjustments based on individual factors, such as life expectancy. It advises on use of metformin as first-line therapy followed by a sodium-glucose cotransporter-2 inhibitor or a glucagon-like peptide-1 agonist for those with established cardiovascular disease or risk factors.

“Cost may be a barrier to taking some [type 2 diabetes] medications as prescribed; however, many of these medications are now more commonly covered by more health insurance plans,” Dr. Joseph said.

“Another barrier is recognition by patients that these newer [type 2 diabetes] medications are also effective in reducing the risk of heart disease, stroke, heart failure, and kidney disease.”

Blood pressure treatment guidelines differ between those of the AHA/American College of Cardiology (ACC) and the American Diabetes Association (ADA), most notably that the AHA/ACC guidelines advise a general target of < 130/80 mm Hg, whereas ADA advises < 140/90 mm Hg or < 130/80 mm Hg for those with high risk if it can be safely achieved.

The decision should be “patient-centered with shared decision-making,” Dr. Joseph and colleagues advised.

For lipid-lowering, the document cites the 2018 ACC/AHA cholesterol guidelines, which include advising statins as first-line therapy for both primary and secondary prevention in diabetes, with highest intensity statins used in those at highest risk. But again, treatment should be individualized, and other agents should be used for patients in whom statins don’t work or aren’t tolerated.

And while use of antiplatelets – that is, aspirin – is well established as secondary prevention in type 2 diabetes, given new data suggesting that the risk for major bleeding could outweigh the benefits for primary prevention, “the relative benefits of antithrombotic approaches need to be weighed carefully against risks using a patient-centered approach,” the authors advised.

Among the many imaging tests available to facilitate cardiovascular risk stratification in type 2 diabetes, coronary artery calcification (CAC) CT screening is one of the few with sufficient data to support routine use in selected patients. The National Lipid Association, for example, recommends escalation to high-intensity statin for CAC > 100.

“One avenue to continue to address and advance diabetes management is through breaking down the four walls of the clinic or hospital through community engagement, clinic-to-community connections, and academic-community-government partnerships that may help address and support modifiable lifestyle behaviors such as physical activity, nutrition, smoking cessation and stress management,” Dr. Joseph concluded.

The AHA receives funding primarily from individuals. Foundations and corporations, including pharmaceutical, device manufacturers, and other companies, also make donations and fund AHA programs and events. The AHA’s strict policies prevent these relationships from influencing the science content. Revenues from pharmaceutical and biotech companies, device manufacturers, and health insurance providers and the AHA’s financial information are available on the association’s website. Dr. Joseph has disclosed no relevant financial relationships.

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

SARS-CoV-2 infection was associated with an increased risk for diabetes among youth, whereas other acute respiratory infections were not, new data from the U.S. Centers for Disease Control and Prevention indicate.

The results from two large U.S. health claims databases were published in an early release in the CDC’s Morbidity and Mortality Weekly Report by Catherine E. Barrett, PhD, and colleagues of the CDC’s COVID-19 Emergency Response Team and Division of Diabetes Translation.

Clinicians should monitor individuals younger than 18 years in the months following a SARS-CoV-2 infection for new diabetes onset, they advise.

The findings, which are supported by independent studies in adults, “underscore the importance of COVID-19 prevention among all age groups, including vaccination for all eligible children and adolescents, and chronic disease prevention and treatment,” Dr. Barrett and colleagues say.

Diabetes type couldn’t be reliably distinguished from the databases, which is noted as an important study limitation.

“SARS-CoV-2 infection might lead to type 1 or type 2 diabetes through complex and differing mechanisms,” they say.

Emerging evidence began to suggest, in mid-2020, that COVID-19 may trigger the onset of diabetes in healthy people. A new global registry was subsequently established to collect data on patients with COVID-19–related diabetes, called the CoviDiab registry.
 

Not clear if diabetes after COVID-19 is transient or permanent

From one of the databases used in the new study, known as IQVIA, 80,893 individuals aged younger than 18 years diagnosed with COVID-19 during March 2020 to February 26, 2021, were compared with age- and sex-matched people during that period who did not have COVID-19 and to prepandemic groups with and without a diagnosis of acute respiratory illness during March 1, 2017, to February 26, 2018.

From the second database, HealthVerity, 439,439 youth diagnosed with COVID-19 during March 1, 2020, to June 28, 2021, were compared with age- and sex-matched youth without COVID-19. Here, there was no prepandemic comparison group.

Diabetes diagnoses were coded in 0.08% with COVID-19 vs. 0.03% without COVID-19 in IQVIA and in 0.25% vs. 0.19% in HealthVerity.

Thus, new diabetes diagnoses were 166% and 31% more likely to occur in those with COVID-19 in IQVIA and HealthVerity, respectively. And in IQVIA, those with COVID-19 were 116% more likely to develop diabetes than were those with prepandemic acute respiratory illnesses. Those differences were all significant, whereas non–SARS-CoV-2 respiratory infections were not associated with diabetes, Dr. Barrett and colleagues say.

In both databases, diabetic ketoacidosis (DKA) was more common at diabetes onset among those with, vs. without, COVID-19: 48.5% vs. 13.6% in IQVIA and 40.2% vs. 29.7% in HealthVerity. In IQVIA, 22.0% with prepandemic acute respiratory illness presented with DKA.

Dr. Barrett and colleagues offer several potential explanations for the observed association between COVID-19 and diabetes, including a direct attack on pancreatic beta cells expressing angiotensin-converting enzyme 2 receptors, or via stress hyperglycemia resulting from cytokine storm and alterations in glucose metabolism.

Another possibility is the precipitation to diabetes from prediabetes; the latter is a condition present in one in five U.S. adolescents.

Steroid treatment during hospitalization might have led to transient hyperglycemia, but only 1.5% to 2.2% of diabetes codes were for drug- or chemical-induced diabetes. The majority were for type 1 or 2.

Alternatively, pandemic-associated weight gain might have also contributed to risks for both severe COVID-19 and type 2 diabetes.

“Although this study can provide information on the risk for diabetes following SARS-CoV-2 infection, additional data are needed to understand underlying pathogenic mechanisms, either those caused by SARS-CoV-2 infection itself or resulting from treatments, and whether a COVID-19–associated diabetes diagnosis is transient or leads to a chronic condition,” Dr. Barrett and colleagues conclude.

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

SARS-CoV-2 infection was associated with an increased risk for diabetes among youth, whereas other acute respiratory infections were not, new data from the U.S. Centers for Disease Control and Prevention indicate.

The results from two large U.S. health claims databases were published in an early release in the CDC’s Morbidity and Mortality Weekly Report by Catherine E. Barrett, PhD, and colleagues of the CDC’s COVID-19 Emergency Response Team and Division of Diabetes Translation.

Clinicians should monitor individuals younger than 18 years in the months following a SARS-CoV-2 infection for new diabetes onset, they advise.

The findings, which are supported by independent studies in adults, “underscore the importance of COVID-19 prevention among all age groups, including vaccination for all eligible children and adolescents, and chronic disease prevention and treatment,” Dr. Barrett and colleagues say.

Diabetes type couldn’t be reliably distinguished from the databases, which is noted as an important study limitation.

“SARS-CoV-2 infection might lead to type 1 or type 2 diabetes through complex and differing mechanisms,” they say.

Emerging evidence began to suggest, in mid-2020, that COVID-19 may trigger the onset of diabetes in healthy people. A new global registry was subsequently established to collect data on patients with COVID-19–related diabetes, called the CoviDiab registry.
 

Not clear if diabetes after COVID-19 is transient or permanent

From one of the databases used in the new study, known as IQVIA, 80,893 individuals aged younger than 18 years diagnosed with COVID-19 during March 2020 to February 26, 2021, were compared with age- and sex-matched people during that period who did not have COVID-19 and to prepandemic groups with and without a diagnosis of acute respiratory illness during March 1, 2017, to February 26, 2018.

From the second database, HealthVerity, 439,439 youth diagnosed with COVID-19 during March 1, 2020, to June 28, 2021, were compared with age- and sex-matched youth without COVID-19. Here, there was no prepandemic comparison group.

Diabetes diagnoses were coded in 0.08% with COVID-19 vs. 0.03% without COVID-19 in IQVIA and in 0.25% vs. 0.19% in HealthVerity.

Thus, new diabetes diagnoses were 166% and 31% more likely to occur in those with COVID-19 in IQVIA and HealthVerity, respectively. And in IQVIA, those with COVID-19 were 116% more likely to develop diabetes than were those with prepandemic acute respiratory illnesses. Those differences were all significant, whereas non–SARS-CoV-2 respiratory infections were not associated with diabetes, Dr. Barrett and colleagues say.

In both databases, diabetic ketoacidosis (DKA) was more common at diabetes onset among those with, vs. without, COVID-19: 48.5% vs. 13.6% in IQVIA and 40.2% vs. 29.7% in HealthVerity. In IQVIA, 22.0% with prepandemic acute respiratory illness presented with DKA.

Dr. Barrett and colleagues offer several potential explanations for the observed association between COVID-19 and diabetes, including a direct attack on pancreatic beta cells expressing angiotensin-converting enzyme 2 receptors, or via stress hyperglycemia resulting from cytokine storm and alterations in glucose metabolism.

Another possibility is the precipitation to diabetes from prediabetes; the latter is a condition present in one in five U.S. adolescents.

Steroid treatment during hospitalization might have led to transient hyperglycemia, but only 1.5% to 2.2% of diabetes codes were for drug- or chemical-induced diabetes. The majority were for type 1 or 2.

Alternatively, pandemic-associated weight gain might have also contributed to risks for both severe COVID-19 and type 2 diabetes.

“Although this study can provide information on the risk for diabetes following SARS-CoV-2 infection, additional data are needed to understand underlying pathogenic mechanisms, either those caused by SARS-CoV-2 infection itself or resulting from treatments, and whether a COVID-19–associated diabetes diagnosis is transient or leads to a chronic condition,” Dr. Barrett and colleagues conclude.

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

SARS-CoV-2 infection was associated with an increased risk for diabetes among youth, whereas other acute respiratory infections were not, new data from the U.S. Centers for Disease Control and Prevention indicate.

The results from two large U.S. health claims databases were published in an early release in the CDC’s Morbidity and Mortality Weekly Report by Catherine E. Barrett, PhD, and colleagues of the CDC’s COVID-19 Emergency Response Team and Division of Diabetes Translation.

Clinicians should monitor individuals younger than 18 years in the months following a SARS-CoV-2 infection for new diabetes onset, they advise.

The findings, which are supported by independent studies in adults, “underscore the importance of COVID-19 prevention among all age groups, including vaccination for all eligible children and adolescents, and chronic disease prevention and treatment,” Dr. Barrett and colleagues say.

Diabetes type couldn’t be reliably distinguished from the databases, which is noted as an important study limitation.

“SARS-CoV-2 infection might lead to type 1 or type 2 diabetes through complex and differing mechanisms,” they say.

Emerging evidence began to suggest, in mid-2020, that COVID-19 may trigger the onset of diabetes in healthy people. A new global registry was subsequently established to collect data on patients with COVID-19–related diabetes, called the CoviDiab registry.
 

Not clear if diabetes after COVID-19 is transient or permanent

From one of the databases used in the new study, known as IQVIA, 80,893 individuals aged younger than 18 years diagnosed with COVID-19 during March 2020 to February 26, 2021, were compared with age- and sex-matched people during that period who did not have COVID-19 and to prepandemic groups with and without a diagnosis of acute respiratory illness during March 1, 2017, to February 26, 2018.

From the second database, HealthVerity, 439,439 youth diagnosed with COVID-19 during March 1, 2020, to June 28, 2021, were compared with age- and sex-matched youth without COVID-19. Here, there was no prepandemic comparison group.

Diabetes diagnoses were coded in 0.08% with COVID-19 vs. 0.03% without COVID-19 in IQVIA and in 0.25% vs. 0.19% in HealthVerity.

Thus, new diabetes diagnoses were 166% and 31% more likely to occur in those with COVID-19 in IQVIA and HealthVerity, respectively. And in IQVIA, those with COVID-19 were 116% more likely to develop diabetes than were those with prepandemic acute respiratory illnesses. Those differences were all significant, whereas non–SARS-CoV-2 respiratory infections were not associated with diabetes, Dr. Barrett and colleagues say.

In both databases, diabetic ketoacidosis (DKA) was more common at diabetes onset among those with, vs. without, COVID-19: 48.5% vs. 13.6% in IQVIA and 40.2% vs. 29.7% in HealthVerity. In IQVIA, 22.0% with prepandemic acute respiratory illness presented with DKA.

Dr. Barrett and colleagues offer several potential explanations for the observed association between COVID-19 and diabetes, including a direct attack on pancreatic beta cells expressing angiotensin-converting enzyme 2 receptors, or via stress hyperglycemia resulting from cytokine storm and alterations in glucose metabolism.

Another possibility is the precipitation to diabetes from prediabetes; the latter is a condition present in one in five U.S. adolescents.

Steroid treatment during hospitalization might have led to transient hyperglycemia, but only 1.5% to 2.2% of diabetes codes were for drug- or chemical-induced diabetes. The majority were for type 1 or 2.

Alternatively, pandemic-associated weight gain might have also contributed to risks for both severe COVID-19 and type 2 diabetes.

“Although this study can provide information on the risk for diabetes following SARS-CoV-2 infection, additional data are needed to understand underlying pathogenic mechanisms, either those caused by SARS-CoV-2 infection itself or resulting from treatments, and whether a COVID-19–associated diabetes diagnosis is transient or leads to a chronic condition,” Dr. Barrett and colleagues conclude.

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

The Centers for Medicare & Medicaid Services has finalized a rule to expand Medicare coverage to include continuous glucose monitoring (CGM) devices that are not approved for making treatment decisions.

Proposed in November 2020, the final CMS rule applies primarily to CGMs that integrate with Medtronic insulin pumps. Those CGMs have not been approved by the Food and Drug Administration to replace the need for fingerstick blood glucose measurements in determining insulin or other glucose-lowering medication dosing.

Other CGM systems, Dexcom G6 and Abbott Libre, have “therapeutic” indications and were already covered under Medicare, as was the combined insulin pump–CGM Tandem Diabetes Care Control-IQ technology system.

The expanded coverage means that people using the Medtronic 770G or 630G hybrid closed-loop insulin delivery systems will receive coverage for all the systems’ components, and that people aging into Medicare won’t lose any coverage for those devices.

Medtronic will continue to offer its CGM Access Discount to all Medicare customers until the ruling takes effect. The proposed rule was finalized on Dec. 21, 2021, and will be effective starting 60 days after official publication.

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

The Centers for Medicare & Medicaid Services has finalized a rule to expand Medicare coverage to include continuous glucose monitoring (CGM) devices that are not approved for making treatment decisions.

Proposed in November 2020, the final CMS rule applies primarily to CGMs that integrate with Medtronic insulin pumps. Those CGMs have not been approved by the Food and Drug Administration to replace the need for fingerstick blood glucose measurements in determining insulin or other glucose-lowering medication dosing.

Other CGM systems, Dexcom G6 and Abbott Libre, have “therapeutic” indications and were already covered under Medicare, as was the combined insulin pump–CGM Tandem Diabetes Care Control-IQ technology system.

The expanded coverage means that people using the Medtronic 770G or 630G hybrid closed-loop insulin delivery systems will receive coverage for all the systems’ components, and that people aging into Medicare won’t lose any coverage for those devices.

Medtronic will continue to offer its CGM Access Discount to all Medicare customers until the ruling takes effect. The proposed rule was finalized on Dec. 21, 2021, and will be effective starting 60 days after official publication.

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

The Centers for Medicare & Medicaid Services has finalized a rule to expand Medicare coverage to include continuous glucose monitoring (CGM) devices that are not approved for making treatment decisions.

Proposed in November 2020, the final CMS rule applies primarily to CGMs that integrate with Medtronic insulin pumps. Those CGMs have not been approved by the Food and Drug Administration to replace the need for fingerstick blood glucose measurements in determining insulin or other glucose-lowering medication dosing.

Other CGM systems, Dexcom G6 and Abbott Libre, have “therapeutic” indications and were already covered under Medicare, as was the combined insulin pump–CGM Tandem Diabetes Care Control-IQ technology system.

The expanded coverage means that people using the Medtronic 770G or 630G hybrid closed-loop insulin delivery systems will receive coverage for all the systems’ components, and that people aging into Medicare won’t lose any coverage for those devices.

Medtronic will continue to offer its CGM Access Discount to all Medicare customers until the ruling takes effect. The proposed rule was finalized on Dec. 21, 2021, and will be effective starting 60 days after official publication.

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

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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