CHICAGO – Treatment of hyperthyroidism with surgery or radioactive iodine significantly extends survival, compared with antithyroid medication, while surgery raises the risk for obesity, new data from a large cohort study suggest.

“I think this is something we need to take into our discussions with patients because treatment for hyperthyroidism is very much individualized decision-making ... The effects on mortality are not usually one of the factors we discuss there. But now, we have strong data from a very large cohort of patients indicating that this is something that does need to be discussed,” lead author Kristien Boelaert, MD, who is the current president of the British Thyroid Association, said in an interview.

Dr. Boelaert presented the findings of the EGRET (Weight Changes, Cardio-Metabolic Risks and Mortality in Patients With Hyperthyroidism) study at the Annual Meeting of the Endocrine Society.

Other notable findings from EGRET were that the patients on antithyroid medication were thinner than expected, suggesting undertreatment, and that no differences were found for major adverse cardiac events (MACE) across the treatment options, leaving unexplained the reasons for the increased mortality in the medicated group.

Asked to comment, session moderator Spyridoula Maraka, MD, said: “I think this is very important work because so far when we counsel our patients about the different treatment modalities we focus more on risk for recurrence and other short-term outcomes.”

“But these data give us a bigger perspective on mortality and cardiovascular outcomes ... We haven’t had such good quality data to accurately counsel our patients,” added Dr. Maraka, of the University of Arkansas for Medical Sciences, Little Rock.
 

Mortality higher for medication-treated, but why?

“Hyperthyroidism or an overactive thyroid gland is common, affecting up to 3% of the population, and is associated with long-term adverse cardiac and metabolic consequences. The optimal treatment choice remains unclear,” explained Dr. Boelaert, professor of endocrinology at the University of Birmingham, England, outlining the reasons they conducted the EGRET study.

The study population was 55,318 patients (77% women) with newly diagnosed hyperthyroidism identified from a U.K. population-based primary care electronic health record database. Of those, 77.8% were treated with antithyroid medication, 14.6% with radioactive iodine, and 7.8% with surgery (total or hemithyroidectomy). The health records were linked with national mortality data and Health Survey England data on body mass index (BMI) for comparison.

Dr. Boelaert noted that the trial design “is the best we have” because a randomized clinical trial comparing hyperthyroid treatments would be extremely difficult given the need to individualize therapy and the impossibility of blinding. On the other hand, with the current study, “it’s certainly the largest patient group we’ve looked at.”

Over an average 12.1 years of follow-up, the proportion of patients who died was 14.1% in the medication group, 18.7% of those who had radioiodine therapy, and 9.2% of those who underwent surgery.

Compared with the number who would have been expected to die based on the general background population, the likelihood of reduced life expectancy for the treated groups was increased 2.10-fold for radioiodine, 2.13-fold for surgery, and 2.71-fold for medication. All were significantly higher than the general population (P < .0001).

After further adjustment for multiple confounders, mortality risk was reduced in patients treated with radioiodine (by 13%) or surgery (by 20%), compared with those treated with antithyroid medication, both significant reductions (P < .0001).

After exclusion of the 3.9% with baseline cardiovascular disease, MACE (defined as cardiovascular death or hospitalization for stroke or myocardial infarction) occurred in 9.9%, 13.4%, and 8.0% of the medication, radioiodine, and surgery groups, respectively.

After adjustments, there were no differences in MACE, compared with medications, with hazard ratios of 1.00 (P = .94) for radioactive iodine and 0.97 for surgery (P = .61).

“We were expecting to see a reduction in cardiovascular events, as previous studies suggest that radioactive iodine patients have fewer cardiovascular deaths. We did not see that but our protocol wasn’t set up to get every single specific cause of death. That will require further ongoing analysis,” said Dr. Boelaert.
 

Weight gain: Worth it for longer life

Compared with the background population, thyroidectomy was associated with an increased likelihood of developing obesity (BMI > 30 kg/m²) in both men (odds ratio, 1.56; P < .001), and women (OR, 1.27; P < .001), while radioiodine increased obesity risk in women (OR, 1.12; P < .001) but not in men (OR, 1.03; P = .55).

Among the women, those treated with antithyroid medications had an average 0.28 kg/m² lower BMI, compared with the background population, and those treated with surgery had a 0.83 kg/m² higher BMI. Both differences were significant (P < .001).

The BMI differences were not significant for radioactive iodine in women and for medications and radioactive iodine in men, although the men treated surgically also had a significantly higher BMI (1.09 kg/m²; P < .001).

“The patients on antithyroid drugs were lighter than we would expect. I think that’s ongoing hyperthyroidism. I strongly believe that ... to get rid of hyperthyroidism you have to make patients hypothyroid ... It’s really important that you get good control,” Dr. Boelaert commented.

Dr. Maraka, who is also endocrine section chief of the Arkansas Veteran’s Healthcare System, Little Rock, commented: “[Dr. Boelaert’s] concern is that the patients on antithyroid drugs are not adequately controlled, and we know very well that uncontrolled hyperthyroidism is associated with increased mortality and increased cardiovascular outcomes. This suggests that if patients are on antithyroid medications, they should at least be monitored very well.”

Regarding the possible cause of the increased mortality, if not cardiovascular, Dr. Maraka also pointed out that typically once antithyroid medications are stopped, about half of patients will stay in remission and the other half will return to hyperthyroidism.

“It might be that this kind of ‘yo-yo’ is what’s actually leading to the increased mortality, compared to patients who had definitive treatment and this problem was taken care of. This is speculation but it might be what we’re seeing,” Dr. Maraka observed.

The BMI differences worked out to a weight gain with surgery of approximately 2.1 kg (4.6 lb) for a woman with a height of 160 cm and 2.4 kg for 170 cm. Among men, those differences were 3.2 kg and 3.5 kg for heights of 170 cm and 190 cm, respectively.

Dr. Boelaert said, “I think we should discuss this with patients. They will say they don’t want to get fat, but the absolute weight gain is ... not that much.”

“I personally think that 2 kg is not a big price to pay to live longer. I hope that’s what we’ll be telling our patients in clinic in the next few years after we get this published.”

Dr. Boelaert and Dr. Maraka have reported no relevant financial relationships.

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

CHICAGO – Treatment of hyperthyroidism with surgery or radioactive iodine significantly extends survival, compared with antithyroid medication, while surgery raises the risk for obesity, new data from a large cohort study suggest.

“I think this is something we need to take into our discussions with patients because treatment for hyperthyroidism is very much individualized decision-making ... The effects on mortality are not usually one of the factors we discuss there. But now, we have strong data from a very large cohort of patients indicating that this is something that does need to be discussed,” lead author Kristien Boelaert, MD, who is the current president of the British Thyroid Association, said in an interview.

Dr. Boelaert presented the findings of the EGRET (Weight Changes, Cardio-Metabolic Risks and Mortality in Patients With Hyperthyroidism) study at the Annual Meeting of the Endocrine Society.

Other notable findings from EGRET were that the patients on antithyroid medication were thinner than expected, suggesting undertreatment, and that no differences were found for major adverse cardiac events (MACE) across the treatment options, leaving unexplained the reasons for the increased mortality in the medicated group.

Asked to comment, session moderator Spyridoula Maraka, MD, said: “I think this is very important work because so far when we counsel our patients about the different treatment modalities we focus more on risk for recurrence and other short-term outcomes.”

“But these data give us a bigger perspective on mortality and cardiovascular outcomes ... We haven’t had such good quality data to accurately counsel our patients,” added Dr. Maraka, of the University of Arkansas for Medical Sciences, Little Rock.
 

Mortality higher for medication-treated, but why?

“Hyperthyroidism or an overactive thyroid gland is common, affecting up to 3% of the population, and is associated with long-term adverse cardiac and metabolic consequences. The optimal treatment choice remains unclear,” explained Dr. Boelaert, professor of endocrinology at the University of Birmingham, England, outlining the reasons they conducted the EGRET study.

The study population was 55,318 patients (77% women) with newly diagnosed hyperthyroidism identified from a U.K. population-based primary care electronic health record database. Of those, 77.8% were treated with antithyroid medication, 14.6% with radioactive iodine, and 7.8% with surgery (total or hemithyroidectomy). The health records were linked with national mortality data and Health Survey England data on body mass index (BMI) for comparison.

Dr. Boelaert noted that the trial design “is the best we have” because a randomized clinical trial comparing hyperthyroid treatments would be extremely difficult given the need to individualize therapy and the impossibility of blinding. On the other hand, with the current study, “it’s certainly the largest patient group we’ve looked at.”

Over an average 12.1 years of follow-up, the proportion of patients who died was 14.1% in the medication group, 18.7% of those who had radioiodine therapy, and 9.2% of those who underwent surgery.

Compared with the number who would have been expected to die based on the general background population, the likelihood of reduced life expectancy for the treated groups was increased 2.10-fold for radioiodine, 2.13-fold for surgery, and 2.71-fold for medication. All were significantly higher than the general population (P < .0001).

After further adjustment for multiple confounders, mortality risk was reduced in patients treated with radioiodine (by 13%) or surgery (by 20%), compared with those treated with antithyroid medication, both significant reductions (P < .0001).

After exclusion of the 3.9% with baseline cardiovascular disease, MACE (defined as cardiovascular death or hospitalization for stroke or myocardial infarction) occurred in 9.9%, 13.4%, and 8.0% of the medication, radioiodine, and surgery groups, respectively.

After adjustments, there were no differences in MACE, compared with medications, with hazard ratios of 1.00 (P = .94) for radioactive iodine and 0.97 for surgery (P = .61).

“We were expecting to see a reduction in cardiovascular events, as previous studies suggest that radioactive iodine patients have fewer cardiovascular deaths. We did not see that but our protocol wasn’t set up to get every single specific cause of death. That will require further ongoing analysis,” said Dr. Boelaert.
 

Weight gain: Worth it for longer life

Compared with the background population, thyroidectomy was associated with an increased likelihood of developing obesity (BMI > 30 kg/m²) in both men (odds ratio, 1.56; P < .001), and women (OR, 1.27; P < .001), while radioiodine increased obesity risk in women (OR, 1.12; P < .001) but not in men (OR, 1.03; P = .55).

Among the women, those treated with antithyroid medications had an average 0.28 kg/m² lower BMI, compared with the background population, and those treated with surgery had a 0.83 kg/m² higher BMI. Both differences were significant (P < .001).

The BMI differences were not significant for radioactive iodine in women and for medications and radioactive iodine in men, although the men treated surgically also had a significantly higher BMI (1.09 kg/m²; P < .001).

“The patients on antithyroid drugs were lighter than we would expect. I think that’s ongoing hyperthyroidism. I strongly believe that ... to get rid of hyperthyroidism you have to make patients hypothyroid ... It’s really important that you get good control,” Dr. Boelaert commented.

Dr. Maraka, who is also endocrine section chief of the Arkansas Veteran’s Healthcare System, Little Rock, commented: “[Dr. Boelaert’s] concern is that the patients on antithyroid drugs are not adequately controlled, and we know very well that uncontrolled hyperthyroidism is associated with increased mortality and increased cardiovascular outcomes. This suggests that if patients are on antithyroid medications, they should at least be monitored very well.”

Regarding the possible cause of the increased mortality, if not cardiovascular, Dr. Maraka also pointed out that typically once antithyroid medications are stopped, about half of patients will stay in remission and the other half will return to hyperthyroidism.

“It might be that this kind of ‘yo-yo’ is what’s actually leading to the increased mortality, compared to patients who had definitive treatment and this problem was taken care of. This is speculation but it might be what we’re seeing,” Dr. Maraka observed.

The BMI differences worked out to a weight gain with surgery of approximately 2.1 kg (4.6 lb) for a woman with a height of 160 cm and 2.4 kg for 170 cm. Among men, those differences were 3.2 kg and 3.5 kg for heights of 170 cm and 190 cm, respectively.

Dr. Boelaert said, “I think we should discuss this with patients. They will say they don’t want to get fat, but the absolute weight gain is ... not that much.”

“I personally think that 2 kg is not a big price to pay to live longer. I hope that’s what we’ll be telling our patients in clinic in the next few years after we get this published.”

Dr. Boelaert and Dr. Maraka have reported no relevant financial relationships.

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

CHICAGO – Treatment of hyperthyroidism with surgery or radioactive iodine significantly extends survival, compared with antithyroid medication, while surgery raises the risk for obesity, new data from a large cohort study suggest.

“I think this is something we need to take into our discussions with patients because treatment for hyperthyroidism is very much individualized decision-making ... The effects on mortality are not usually one of the factors we discuss there. But now, we have strong data from a very large cohort of patients indicating that this is something that does need to be discussed,” lead author Kristien Boelaert, MD, who is the current president of the British Thyroid Association, said in an interview.

Dr. Boelaert presented the findings of the EGRET (Weight Changes, Cardio-Metabolic Risks and Mortality in Patients With Hyperthyroidism) study at the Annual Meeting of the Endocrine Society.

Other notable findings from EGRET were that the patients on antithyroid medication were thinner than expected, suggesting undertreatment, and that no differences were found for major adverse cardiac events (MACE) across the treatment options, leaving unexplained the reasons for the increased mortality in the medicated group.

Asked to comment, session moderator Spyridoula Maraka, MD, said: “I think this is very important work because so far when we counsel our patients about the different treatment modalities we focus more on risk for recurrence and other short-term outcomes.”

“But these data give us a bigger perspective on mortality and cardiovascular outcomes ... We haven’t had such good quality data to accurately counsel our patients,” added Dr. Maraka, of the University of Arkansas for Medical Sciences, Little Rock.
 

Mortality higher for medication-treated, but why?

“Hyperthyroidism or an overactive thyroid gland is common, affecting up to 3% of the population, and is associated with long-term adverse cardiac and metabolic consequences. The optimal treatment choice remains unclear,” explained Dr. Boelaert, professor of endocrinology at the University of Birmingham, England, outlining the reasons they conducted the EGRET study.

The study population was 55,318 patients (77% women) with newly diagnosed hyperthyroidism identified from a U.K. population-based primary care electronic health record database. Of those, 77.8% were treated with antithyroid medication, 14.6% with radioactive iodine, and 7.8% with surgery (total or hemithyroidectomy). The health records were linked with national mortality data and Health Survey England data on body mass index (BMI) for comparison.

Dr. Boelaert noted that the trial design “is the best we have” because a randomized clinical trial comparing hyperthyroid treatments would be extremely difficult given the need to individualize therapy and the impossibility of blinding. On the other hand, with the current study, “it’s certainly the largest patient group we’ve looked at.”

Over an average 12.1 years of follow-up, the proportion of patients who died was 14.1% in the medication group, 18.7% of those who had radioiodine therapy, and 9.2% of those who underwent surgery.

Compared with the number who would have been expected to die based on the general background population, the likelihood of reduced life expectancy for the treated groups was increased 2.10-fold for radioiodine, 2.13-fold for surgery, and 2.71-fold for medication. All were significantly higher than the general population (P < .0001).

After further adjustment for multiple confounders, mortality risk was reduced in patients treated with radioiodine (by 13%) or surgery (by 20%), compared with those treated with antithyroid medication, both significant reductions (P < .0001).

After exclusion of the 3.9% with baseline cardiovascular disease, MACE (defined as cardiovascular death or hospitalization for stroke or myocardial infarction) occurred in 9.9%, 13.4%, and 8.0% of the medication, radioiodine, and surgery groups, respectively.

After adjustments, there were no differences in MACE, compared with medications, with hazard ratios of 1.00 (P = .94) for radioactive iodine and 0.97 for surgery (P = .61).

“We were expecting to see a reduction in cardiovascular events, as previous studies suggest that radioactive iodine patients have fewer cardiovascular deaths. We did not see that but our protocol wasn’t set up to get every single specific cause of death. That will require further ongoing analysis,” said Dr. Boelaert.
 

Weight gain: Worth it for longer life

Compared with the background population, thyroidectomy was associated with an increased likelihood of developing obesity (BMI > 30 kg/m²) in both men (odds ratio, 1.56; P < .001), and women (OR, 1.27; P < .001), while radioiodine increased obesity risk in women (OR, 1.12; P < .001) but not in men (OR, 1.03; P = .55).

Among the women, those treated with antithyroid medications had an average 0.28 kg/m² lower BMI, compared with the background population, and those treated with surgery had a 0.83 kg/m² higher BMI. Both differences were significant (P < .001).

The BMI differences were not significant for radioactive iodine in women and for medications and radioactive iodine in men, although the men treated surgically also had a significantly higher BMI (1.09 kg/m²; P < .001).

“The patients on antithyroid drugs were lighter than we would expect. I think that’s ongoing hyperthyroidism. I strongly believe that ... to get rid of hyperthyroidism you have to make patients hypothyroid ... It’s really important that you get good control,” Dr. Boelaert commented.

Dr. Maraka, who is also endocrine section chief of the Arkansas Veteran’s Healthcare System, Little Rock, commented: “[Dr. Boelaert’s] concern is that the patients on antithyroid drugs are not adequately controlled, and we know very well that uncontrolled hyperthyroidism is associated with increased mortality and increased cardiovascular outcomes. This suggests that if patients are on antithyroid medications, they should at least be monitored very well.”

Regarding the possible cause of the increased mortality, if not cardiovascular, Dr. Maraka also pointed out that typically once antithyroid medications are stopped, about half of patients will stay in remission and the other half will return to hyperthyroidism.

“It might be that this kind of ‘yo-yo’ is what’s actually leading to the increased mortality, compared to patients who had definitive treatment and this problem was taken care of. This is speculation but it might be what we’re seeing,” Dr. Maraka observed.

The BMI differences worked out to a weight gain with surgery of approximately 2.1 kg (4.6 lb) for a woman with a height of 160 cm and 2.4 kg for 170 cm. Among men, those differences were 3.2 kg and 3.5 kg for heights of 170 cm and 190 cm, respectively.

Dr. Boelaert said, “I think we should discuss this with patients. They will say they don’t want to get fat, but the absolute weight gain is ... not that much.”

“I personally think that 2 kg is not a big price to pay to live longer. I hope that’s what we’ll be telling our patients in clinic in the next few years after we get this published.”

Dr. Boelaert and Dr. Maraka have reported no relevant financial relationships.

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

SAN DIEGO – Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 U.S. children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening hemoglobin A1c levels, said Rachelle G. Gandica, MD, at the annual scientific sessions of the American Diabetes Association.

Indeed, an A1c greater than 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Dr. Gandica. “I teach fellows this all the time, that if a child’s A1c is above 6.2% they will fail, and you have to watch for that,” she noted.

Mitchel L. Zoler/Medscape

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed, for example, an overall cardiovascular event rate of 3.7/1,000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Dr. Gandica called these and other findings “sobering details” that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study – when their diabetes had been diagnosed for an average of about 8 months – and then underwent an average 12.6 years of follow-up.

Investigators also found:

• After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
• Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
• Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
• Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire prognosis a reason to aggressively treat these patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists, said Dr. Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York.

“It’s fair to say we now more aggressively use [these agents] in children,” she said in an interview, and noted the very recent approval, just last week, by the U.S. Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years.

“I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits,” Dr. Gandica said.

Other newer type 2 diabetes medications approved for U.S. children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.
 

A1c spike heralds treatment failure: ‘Watch for that’

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 U.S. sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any preexisting antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012 in the New England Journal of Medicine

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findingsshow that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That’s an important message for clinicians, Dr. Gandica concluded.

TODAY and TODAY2 received no commercial funding. Dr. Gandica has reported no relevant financial relationships.

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

SAN DIEGO – Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 U.S. children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening hemoglobin A1c levels, said Rachelle G. Gandica, MD, at the annual scientific sessions of the American Diabetes Association.

Indeed, an A1c greater than 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Dr. Gandica. “I teach fellows this all the time, that if a child’s A1c is above 6.2% they will fail, and you have to watch for that,” she noted.

Mitchel L. Zoler/Medscape

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed, for example, an overall cardiovascular event rate of 3.7/1,000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Dr. Gandica called these and other findings “sobering details” that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study – when their diabetes had been diagnosed for an average of about 8 months – and then underwent an average 12.6 years of follow-up.

Investigators also found:

• After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
• Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
• Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
• Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire prognosis a reason to aggressively treat these patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists, said Dr. Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York.

“It’s fair to say we now more aggressively use [these agents] in children,” she said in an interview, and noted the very recent approval, just last week, by the U.S. Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years.

“I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits,” Dr. Gandica said.

Other newer type 2 diabetes medications approved for U.S. children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.
 

A1c spike heralds treatment failure: ‘Watch for that’

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 U.S. sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any preexisting antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012 in the New England Journal of Medicine

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findingsshow that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That’s an important message for clinicians, Dr. Gandica concluded.

TODAY and TODAY2 received no commercial funding. Dr. Gandica has reported no relevant financial relationships.

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

SAN DIEGO – Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 U.S. children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening hemoglobin A1c levels, said Rachelle G. Gandica, MD, at the annual scientific sessions of the American Diabetes Association.

Indeed, an A1c greater than 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Dr. Gandica. “I teach fellows this all the time, that if a child’s A1c is above 6.2% they will fail, and you have to watch for that,” she noted.

Mitchel L. Zoler/Medscape

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed, for example, an overall cardiovascular event rate of 3.7/1,000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Dr. Gandica called these and other findings “sobering details” that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study – when their diabetes had been diagnosed for an average of about 8 months – and then underwent an average 12.6 years of follow-up.

Investigators also found:

• After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
• Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
• Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
• Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire prognosis a reason to aggressively treat these patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists, said Dr. Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York.

“It’s fair to say we now more aggressively use [these agents] in children,” she said in an interview, and noted the very recent approval, just last week, by the U.S. Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years.

“I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits,” Dr. Gandica said.

Other newer type 2 diabetes medications approved for U.S. children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.
 

A1c spike heralds treatment failure: ‘Watch for that’

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 U.S. sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any preexisting antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012 in the New England Journal of Medicine

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findingsshow that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That’s an important message for clinicians, Dr. Gandica concluded.

TODAY and TODAY2 received no commercial funding. Dr. Gandica has reported no relevant financial relationships.

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

SAN DIEGO – Coadministration of the long-acting amylin analog cagrilintide plus the glucagonlike peptide–1 (GLP-1) agonist semaglutide, dubbed CagriSema, resulted in significantly greater weight loss, along with improved measures of glucose control, than either agent alone, in a small, short phase 2 trial of patients with type 2 diabetes. 

Juan P. Frias, MD, presented the findings at the annual scientific sessions of the American Diabetes Association, which were simultaneously published in The Lancet.

“Overall, in this phase 2 trial in people with type 2 diabetes, clinically relevant improvements in glycemic control – as assessed by [hemoglobin] A1c, [time in range], and other [continuous glucose monitoring (CGM)] measures – were observed with CagriSema, as well as weight loss of a magnitude not previously reported with pharmacotherapies in this population. CagriSema also had an acceptable safety profile,” the researchers summarized.

“These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies,” said Dr. Frias, from Velocity Clinical Research, Los Angeles.

In reply to audience questions, he said he was “pleasantly surprised” with the low gastrointestinal adverse events, which may have been related to the slower dosing titration. He also noted that patients in the study did not receive dietary counseling, unlike in the STEP-2 trial, where weight loss with semaglutide was greater than in this study.  

Time in normal blood glucose range in the CagriSema group went from 40% at baseline to 89% at week 32, Chantal Mathieu, MD, PhD, reported during a follow-up presentation that focused on the trial’s CGM findings.

“I was extremely happy that we were allowed to include CGM measurement because it does give you more information, especially in a short-term trial,” said Dr. Mathieu, from the Katholieke Universiteit Leuven (Belgium). The CGM data were collected for 10 days preceding baseline and at weeks 20 and 32.

“At this point in time, it is difficult to make a final determination” about potential future clinical applications, session chair Elisabetta Patorno, MD, DrPH, from Harvard Medical School, Boston, said in an interview. “This was a phase 2 randomized controlled trial, so more patients are needed.

“It’s very interesting what was found with the use of CGM, which makes us think whether they should always be part of [trials] versus the more traditional A1c assessment,” Dr. Patorno added.
 

‘Synergistic effect for both glycemic control and weight loss’

“CagriSema is the next in a series of gut hormone analogs with the potential to herald a new era in treating obesity and preventing diabesity,” the coexistence of type 2 diabetes and obesity, Caroline M. Apovian, MD, and Marie E. McDonnell, MD, both also from Harvard Medical School, wrote in an accompanying editorial in The Lancet.

Cagrilintide plus semaglutide each “effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain,” they noted.

The results – a substantial difference in effect size between the combination drug and each component alone – show that “there is a synergistic effect for both glycemic control and weight loss.

“The weight loss seen in this phase 2 trial of CagriSema in 32 weeks could predict a phase 3 trial result over 1 year that might surpass that of semaglutide (14.9%) and tirzepatide (20.9%) in a population without type 2 diabetes, and might equal that of bariatric surgery (23.5%-30.4%),” they speculated.

However, it’s still early days, the editorialists cautioned. Study limitations include that it was a small trial and the mean duration of type 2 diabetes at baseline was shorter in the CagriSema group (6.4 years) than in the semaglutide or cagrilintide alone groups (9.2 years and 10.7 years, respectively).

The rate of gastrointestinal adverse events was also higher in the CagriSema group (58%) than in the other two groups (about 33%). However, the adverse events “were all mild or moderate and not severe enough to lead to participant withdrawal,” they noted. “Remarkably, only one participant, from the semaglutide group, withdrew due to adverse events during the 32-week trial across all groups.

“Although bariatric surgery remains the most effective treatment for severe obesity, offering the most robust weight reduction, remission of type 2 diabetes, and reduced cardiovascular mortality,” the study suggests that “combination metabolic hormonal therapy could offer all three of these outcomes in the near future,” Dr. Apovian and Dr. McDonnell wrote.
 

92 patients randomized to three treatments

In the study, researchers randomized 92 adults with type 2 diabetes and a body mass index of at least 27 kg/m² taking metformin alone (73%) or metformin plus a sodium-glucose cotransporter 2 inhibitor (27%), at 17 sites in the United States, between August and October 2021.

Patients were a mean age of 58 years and 64% were men. Mean A1c was 8.4% and mean bodyweight was 106 kg (234 lb).

They were randomized 1:1:1 to receive up to maximal once-weekly doses of 2.4 mg semaglutide and 2.4 mg cagrilintide (CagriSema, given in two injector pens), 2.4 mg semaglutide (plus placebo), or 2.4 mg cagrilintide (plus placebo).

Both cagrilintide and semaglutide are manufactured by the Danish company Novo Nordisk. Semaglutide is already approved in the United States for type 2 diabetes, as Ozempic, and as the weight-loss drug Wegovy. Cagrilintide is not yet approved.

Treatment doses were escalated every 4 weeks from 0.25 to 0.5 to 1.0 to 1.7 mg to a maintenance dose of 2.4 mg at 16 weeks. Patients then entered a 16-week maintenance phase followed by a 5-week follow-up period.

Among the key findings, the reduction in A1c at 32 weeks, compared with baseline (primary outcome), was –2.2% with CagriSema, –1.8% with semaglutide, and –0.9% with cagrilintide, but was not significantly greater with CagriSema versus semaglutide (–0.4%; P = .07).

However, in a secondary outcome, there was a significantly greater difference in A1c at 32 weeks with CagriSema versus cagrilintide (–1.3%; P < .0001). Moreover, 89% of patients in the CagriSema group reached an A1c less than 7%.

In other secondary outcomes, there was a significantly greater reduction in body weight at 32 weeks with CagriSema versus cagrilintide or semaglutide, with 71% of patients in the CagriSema group achieving greater than 10% reduction in body weight. Patients in the CagriSema group also had clinically relevant improvements in blood pressure, lipids, and high-sensitivity C-reactive protein.

Adverse events – reported in 68% of patients with CagriSema versus 71% with semaglutide and 80% with cagrilintide – were mostly mild or moderate gastrointestinal events, consistent with those seen in these two drug classes.

At week 32, time in range was 89% with CagriSema versus 76% with semaglutide and 72% with cagrilintide.

“Our phase 2 clinical trial is the first study to report efficacy and safety data for treatment with the combination of a GLP-1 agonist and an amylin analog in participants with type 2 diabetes,” the researchers summarize. “These data support further investigation of CagriSema in this population in longer and larger phase 3 studies.”

This trial was sponsored by Novo Nordisk. Dr. Frias, Dr. Mathieu, Dr. Apovian, and Dr. McDonnell reported financial relationships with a number of companies.

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

SAN DIEGO – Coadministration of the long-acting amylin analog cagrilintide plus the glucagonlike peptide–1 (GLP-1) agonist semaglutide, dubbed CagriSema, resulted in significantly greater weight loss, along with improved measures of glucose control, than either agent alone, in a small, short phase 2 trial of patients with type 2 diabetes. 

Juan P. Frias, MD, presented the findings at the annual scientific sessions of the American Diabetes Association, which were simultaneously published in The Lancet.

“Overall, in this phase 2 trial in people with type 2 diabetes, clinically relevant improvements in glycemic control – as assessed by [hemoglobin] A1c, [time in range], and other [continuous glucose monitoring (CGM)] measures – were observed with CagriSema, as well as weight loss of a magnitude not previously reported with pharmacotherapies in this population. CagriSema also had an acceptable safety profile,” the researchers summarized.

“These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies,” said Dr. Frias, from Velocity Clinical Research, Los Angeles.

In reply to audience questions, he said he was “pleasantly surprised” with the low gastrointestinal adverse events, which may have been related to the slower dosing titration. He also noted that patients in the study did not receive dietary counseling, unlike in the STEP-2 trial, where weight loss with semaglutide was greater than in this study.  

Time in normal blood glucose range in the CagriSema group went from 40% at baseline to 89% at week 32, Chantal Mathieu, MD, PhD, reported during a follow-up presentation that focused on the trial’s CGM findings.

“I was extremely happy that we were allowed to include CGM measurement because it does give you more information, especially in a short-term trial,” said Dr. Mathieu, from the Katholieke Universiteit Leuven (Belgium). The CGM data were collected for 10 days preceding baseline and at weeks 20 and 32.

“At this point in time, it is difficult to make a final determination” about potential future clinical applications, session chair Elisabetta Patorno, MD, DrPH, from Harvard Medical School, Boston, said in an interview. “This was a phase 2 randomized controlled trial, so more patients are needed.

“It’s very interesting what was found with the use of CGM, which makes us think whether they should always be part of [trials] versus the more traditional A1c assessment,” Dr. Patorno added.
 

‘Synergistic effect for both glycemic control and weight loss’

“CagriSema is the next in a series of gut hormone analogs with the potential to herald a new era in treating obesity and preventing diabesity,” the coexistence of type 2 diabetes and obesity, Caroline M. Apovian, MD, and Marie E. McDonnell, MD, both also from Harvard Medical School, wrote in an accompanying editorial in The Lancet.

Cagrilintide plus semaglutide each “effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain,” they noted.

The results – a substantial difference in effect size between the combination drug and each component alone – show that “there is a synergistic effect for both glycemic control and weight loss.

“The weight loss seen in this phase 2 trial of CagriSema in 32 weeks could predict a phase 3 trial result over 1 year that might surpass that of semaglutide (14.9%) and tirzepatide (20.9%) in a population without type 2 diabetes, and might equal that of bariatric surgery (23.5%-30.4%),” they speculated.

However, it’s still early days, the editorialists cautioned. Study limitations include that it was a small trial and the mean duration of type 2 diabetes at baseline was shorter in the CagriSema group (6.4 years) than in the semaglutide or cagrilintide alone groups (9.2 years and 10.7 years, respectively).

The rate of gastrointestinal adverse events was also higher in the CagriSema group (58%) than in the other two groups (about 33%). However, the adverse events “were all mild or moderate and not severe enough to lead to participant withdrawal,” they noted. “Remarkably, only one participant, from the semaglutide group, withdrew due to adverse events during the 32-week trial across all groups.

“Although bariatric surgery remains the most effective treatment for severe obesity, offering the most robust weight reduction, remission of type 2 diabetes, and reduced cardiovascular mortality,” the study suggests that “combination metabolic hormonal therapy could offer all three of these outcomes in the near future,” Dr. Apovian and Dr. McDonnell wrote.
 

92 patients randomized to three treatments

In the study, researchers randomized 92 adults with type 2 diabetes and a body mass index of at least 27 kg/m² taking metformin alone (73%) or metformin plus a sodium-glucose cotransporter 2 inhibitor (27%), at 17 sites in the United States, between August and October 2021.

Patients were a mean age of 58 years and 64% were men. Mean A1c was 8.4% and mean bodyweight was 106 kg (234 lb).

They were randomized 1:1:1 to receive up to maximal once-weekly doses of 2.4 mg semaglutide and 2.4 mg cagrilintide (CagriSema, given in two injector pens), 2.4 mg semaglutide (plus placebo), or 2.4 mg cagrilintide (plus placebo).

Both cagrilintide and semaglutide are manufactured by the Danish company Novo Nordisk. Semaglutide is already approved in the United States for type 2 diabetes, as Ozempic, and as the weight-loss drug Wegovy. Cagrilintide is not yet approved.

Treatment doses were escalated every 4 weeks from 0.25 to 0.5 to 1.0 to 1.7 mg to a maintenance dose of 2.4 mg at 16 weeks. Patients then entered a 16-week maintenance phase followed by a 5-week follow-up period.

Among the key findings, the reduction in A1c at 32 weeks, compared with baseline (primary outcome), was –2.2% with CagriSema, –1.8% with semaglutide, and –0.9% with cagrilintide, but was not significantly greater with CagriSema versus semaglutide (–0.4%; P = .07).

However, in a secondary outcome, there was a significantly greater difference in A1c at 32 weeks with CagriSema versus cagrilintide (–1.3%; P < .0001). Moreover, 89% of patients in the CagriSema group reached an A1c less than 7%.

In other secondary outcomes, there was a significantly greater reduction in body weight at 32 weeks with CagriSema versus cagrilintide or semaglutide, with 71% of patients in the CagriSema group achieving greater than 10% reduction in body weight. Patients in the CagriSema group also had clinically relevant improvements in blood pressure, lipids, and high-sensitivity C-reactive protein.

Adverse events – reported in 68% of patients with CagriSema versus 71% with semaglutide and 80% with cagrilintide – were mostly mild or moderate gastrointestinal events, consistent with those seen in these two drug classes.

At week 32, time in range was 89% with CagriSema versus 76% with semaglutide and 72% with cagrilintide.

“Our phase 2 clinical trial is the first study to report efficacy and safety data for treatment with the combination of a GLP-1 agonist and an amylin analog in participants with type 2 diabetes,” the researchers summarize. “These data support further investigation of CagriSema in this population in longer and larger phase 3 studies.”

This trial was sponsored by Novo Nordisk. Dr. Frias, Dr. Mathieu, Dr. Apovian, and Dr. McDonnell reported financial relationships with a number of companies.

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

SAN DIEGO – Coadministration of the long-acting amylin analog cagrilintide plus the glucagonlike peptide–1 (GLP-1) agonist semaglutide, dubbed CagriSema, resulted in significantly greater weight loss, along with improved measures of glucose control, than either agent alone, in a small, short phase 2 trial of patients with type 2 diabetes. 

Juan P. Frias, MD, presented the findings at the annual scientific sessions of the American Diabetes Association, which were simultaneously published in The Lancet.

“Overall, in this phase 2 trial in people with type 2 diabetes, clinically relevant improvements in glycemic control – as assessed by [hemoglobin] A1c, [time in range], and other [continuous glucose monitoring (CGM)] measures – were observed with CagriSema, as well as weight loss of a magnitude not previously reported with pharmacotherapies in this population. CagriSema also had an acceptable safety profile,” the researchers summarized.

“These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies,” said Dr. Frias, from Velocity Clinical Research, Los Angeles.

In reply to audience questions, he said he was “pleasantly surprised” with the low gastrointestinal adverse events, which may have been related to the slower dosing titration. He also noted that patients in the study did not receive dietary counseling, unlike in the STEP-2 trial, where weight loss with semaglutide was greater than in this study.  

Time in normal blood glucose range in the CagriSema group went from 40% at baseline to 89% at week 32, Chantal Mathieu, MD, PhD, reported during a follow-up presentation that focused on the trial’s CGM findings.

“I was extremely happy that we were allowed to include CGM measurement because it does give you more information, especially in a short-term trial,” said Dr. Mathieu, from the Katholieke Universiteit Leuven (Belgium). The CGM data were collected for 10 days preceding baseline and at weeks 20 and 32.

“At this point in time, it is difficult to make a final determination” about potential future clinical applications, session chair Elisabetta Patorno, MD, DrPH, from Harvard Medical School, Boston, said in an interview. “This was a phase 2 randomized controlled trial, so more patients are needed.

“It’s very interesting what was found with the use of CGM, which makes us think whether they should always be part of [trials] versus the more traditional A1c assessment,” Dr. Patorno added.
 

‘Synergistic effect for both glycemic control and weight loss’

“CagriSema is the next in a series of gut hormone analogs with the potential to herald a new era in treating obesity and preventing diabesity,” the coexistence of type 2 diabetes and obesity, Caroline M. Apovian, MD, and Marie E. McDonnell, MD, both also from Harvard Medical School, wrote in an accompanying editorial in The Lancet.

Cagrilintide plus semaglutide each “effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain,” they noted.

The results – a substantial difference in effect size between the combination drug and each component alone – show that “there is a synergistic effect for both glycemic control and weight loss.

“The weight loss seen in this phase 2 trial of CagriSema in 32 weeks could predict a phase 3 trial result over 1 year that might surpass that of semaglutide (14.9%) and tirzepatide (20.9%) in a population without type 2 diabetes, and might equal that of bariatric surgery (23.5%-30.4%),” they speculated.

However, it’s still early days, the editorialists cautioned. Study limitations include that it was a small trial and the mean duration of type 2 diabetes at baseline was shorter in the CagriSema group (6.4 years) than in the semaglutide or cagrilintide alone groups (9.2 years and 10.7 years, respectively).

The rate of gastrointestinal adverse events was also higher in the CagriSema group (58%) than in the other two groups (about 33%). However, the adverse events “were all mild or moderate and not severe enough to lead to participant withdrawal,” they noted. “Remarkably, only one participant, from the semaglutide group, withdrew due to adverse events during the 32-week trial across all groups.

“Although bariatric surgery remains the most effective treatment for severe obesity, offering the most robust weight reduction, remission of type 2 diabetes, and reduced cardiovascular mortality,” the study suggests that “combination metabolic hormonal therapy could offer all three of these outcomes in the near future,” Dr. Apovian and Dr. McDonnell wrote.
 

92 patients randomized to three treatments

In the study, researchers randomized 92 adults with type 2 diabetes and a body mass index of at least 27 kg/m² taking metformin alone (73%) or metformin plus a sodium-glucose cotransporter 2 inhibitor (27%), at 17 sites in the United States, between August and October 2021.

Patients were a mean age of 58 years and 64% were men. Mean A1c was 8.4% and mean bodyweight was 106 kg (234 lb).

They were randomized 1:1:1 to receive up to maximal once-weekly doses of 2.4 mg semaglutide and 2.4 mg cagrilintide (CagriSema, given in two injector pens), 2.4 mg semaglutide (plus placebo), or 2.4 mg cagrilintide (plus placebo).

Both cagrilintide and semaglutide are manufactured by the Danish company Novo Nordisk. Semaglutide is already approved in the United States for type 2 diabetes, as Ozempic, and as the weight-loss drug Wegovy. Cagrilintide is not yet approved.

Treatment doses were escalated every 4 weeks from 0.25 to 0.5 to 1.0 to 1.7 mg to a maintenance dose of 2.4 mg at 16 weeks. Patients then entered a 16-week maintenance phase followed by a 5-week follow-up period.

Among the key findings, the reduction in A1c at 32 weeks, compared with baseline (primary outcome), was –2.2% with CagriSema, –1.8% with semaglutide, and –0.9% with cagrilintide, but was not significantly greater with CagriSema versus semaglutide (–0.4%; P = .07).

However, in a secondary outcome, there was a significantly greater difference in A1c at 32 weeks with CagriSema versus cagrilintide (–1.3%; P < .0001). Moreover, 89% of patients in the CagriSema group reached an A1c less than 7%.

In other secondary outcomes, there was a significantly greater reduction in body weight at 32 weeks with CagriSema versus cagrilintide or semaglutide, with 71% of patients in the CagriSema group achieving greater than 10% reduction in body weight. Patients in the CagriSema group also had clinically relevant improvements in blood pressure, lipids, and high-sensitivity C-reactive protein.

Adverse events – reported in 68% of patients with CagriSema versus 71% with semaglutide and 80% with cagrilintide – were mostly mild or moderate gastrointestinal events, consistent with those seen in these two drug classes.

At week 32, time in range was 89% with CagriSema versus 76% with semaglutide and 72% with cagrilintide.

“Our phase 2 clinical trial is the first study to report efficacy and safety data for treatment with the combination of a GLP-1 agonist and an amylin analog in participants with type 2 diabetes,” the researchers summarize. “These data support further investigation of CagriSema in this population in longer and larger phase 3 studies.”

This trial was sponsored by Novo Nordisk. Dr. Frias, Dr. Mathieu, Dr. Apovian, and Dr. McDonnell reported financial relationships with a number of companies.

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

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

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

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

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

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

PHOENIX – The way Jennifer Barton, PhD, sees it, optical coherence tomography (OCT), laser-induced fluorescence, and multiphoton microscopy are poised to revolutionize the future of cancer detection.

Chris Richards/University of Arizona

In a lecture during a multispecialty roundup of cutting-edge energy-based device applications at the annual conference of the American Society for Laser Medicine and Surgery, Dr. Barton, a biomedical engineer who directs the BIO5 Institute at the University of Arizona, Tucson, said that while no current modality exists to enable physicians in dermatology and other specialties to view internal structures throughout the entire body with cellular resolution, refining existing technologies is a good way to start.

In 2011, renowned cancer researchers Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, proposed six hallmarks of cancer, which include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Each hallmark poses unique imaging challenges. For example, enabling replicative immortality “means that the cell nuclei change size and shape; they change their position,” said Dr. Barton, who is also professor of biomedical engineering and optical sciences at the university. “If we want to see that, we’re going to need an imaging modality that’s subcellular in resolution.”

Similarly, if clinicians want to view how proliferative signaling is changing, “that means being able to visualize the cell surface receptors; those are even smaller to actually visualize,” she said. “But we have technologies where we can target those receptors with fluorophores. And then we can look at large areas very quickly.” Meanwhile, the ability of cancer cells to resist cell death and evade growth suppressors often results in thickening of epithelium throughout the body. “So, if we can measure the thickness of the epithelium, we can see that there’s something wrong with that tissue,” she said.

As for cancer’s propensity for invasion and metastasis, “here, we’re looking at how the collagen structure [between the cells] has changed and whether there’s layer breakdown or not. Optical imaging can detect cancer. However, high resolution optical techniques can only image about 1 mm deep, so unless you’re looking at the skin or the eye, you’re going to have to develop an endoscope to be able to view these hallmarks.”

OCT images the tissue microstructure, generally in a resolution of 2-20 microns, at a depth of 1-2 mm, and it measures reflected light. When possible, Dr. Barton combines OCT with laser-induced fluorescence for enhanced accuracy of detection of cancer. Induced fluorescence senses molecular information with the natural fluorophores in the body or with targeted exogenous agents. Then there’s multiphoton microscopy, an advanced imaging technique that enables clinicians to view cellular and subcellular events within living tissue. Early models of this technology “took up entire benches” in physics labs, Dr. Barton said, but she and other investigators are designing smaller devices for use in clinics. “This is exciting, because not only do we [view] subcellular structure with this modality, but it can also be highly sensitive to collagen structure,” she said.
 

Ovarian cancer model

In a model of ovarian cancer, she and colleagues externalized the ovaries of a mouse, imaged the organs, put them back in, and reassessed them at 8 weeks. “This model develops cancer very quickly,” said Dr. Barton, who once worked for McDonnell Douglas on the Space Station program. At 8 weeks, using fluorescence and targeted agents with a tabletop multiphoton microscopy system, they observed that the proliferation signals of cancer had begun. “So, with an agent targeted to the folate receptor or to other receptors that are implicated in cancer development, we can see that ovaries and fallopian tubes are lighting up,” she said.

With proof of concept established with the mouse study, she and other researchers are drawing from technological advances to create tiny laser systems for use in the clinic to image a variety of structures in the human body. Optics advances include bulk optics and all-fiber designs where engineers can create an imaging probe that’s only 125 microns in diameter, “or maybe even as small as 70 microns in diameter,” she said. “We can do fabrications on the tips of endoscopes to redirect the light and focus it. We can also do 3-D printing and spiral scanning to create miniature devices to make new advances. That means that instead of just white light imaging of the colon or the lung like we have had in the past, we can start moving into smaller structures, such as the eustachian tube, the fallopian tube, the bile ducts, or making miniature devices for brain biopsies, lung biopsies, and maybe being able to get into bronchioles and arterioles.”

According to Dr. Barton, prior research has demonstrated that cerebral vasculature can be imaged with a catheter 400 microns in diameter, the spaces in the lungs can be imaged with a needle that is 310 microns in diameter, and the inner structures of the eustachian tube can be viewed with an endoscope 1 mm in diameter.

She and her colleagues are developing an OCT/fluorescence imaging falloposcope that is 0.8 mm in diameter, flexible, and steerable, as a tool for early detection of ovarian cancer in humans. “It’s now known that most ovarian cancer starts in the fallopian tubes,” Dr. Barton said. “It’s metastatic disease when those cells break off from the fallopian tubes and go to the ovaries. We wanted to create an imaging system where we created a fiber bundle that we could navigate with white light and with fluorescence so that we can see these early stages of cancer [and] how they fluoresce differently. We also wanted to have an OCT system so that we could image through the wall of the fallopian tube and look for that layer thickening and other precursors to ovarian cancer.”

To date, in vivo testing in healthy women has demonstrated that the miniature endoscope is able to reach the fallopian tubes through the natural orifice of the vagina and uterus. “That is pretty exciting,” she said. “The images may not be of the highest quality, but we are advancing.”

Dr. Barton reported having no relevant financial disclosures.

PHOENIX – The way Jennifer Barton, PhD, sees it, optical coherence tomography (OCT), laser-induced fluorescence, and multiphoton microscopy are poised to revolutionize the future of cancer detection.

Chris Richards/University of Arizona

In a lecture during a multispecialty roundup of cutting-edge energy-based device applications at the annual conference of the American Society for Laser Medicine and Surgery, Dr. Barton, a biomedical engineer who directs the BIO5 Institute at the University of Arizona, Tucson, said that while no current modality exists to enable physicians in dermatology and other specialties to view internal structures throughout the entire body with cellular resolution, refining existing technologies is a good way to start.

In 2011, renowned cancer researchers Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, proposed six hallmarks of cancer, which include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Each hallmark poses unique imaging challenges. For example, enabling replicative immortality “means that the cell nuclei change size and shape; they change their position,” said Dr. Barton, who is also professor of biomedical engineering and optical sciences at the university. “If we want to see that, we’re going to need an imaging modality that’s subcellular in resolution.”

Similarly, if clinicians want to view how proliferative signaling is changing, “that means being able to visualize the cell surface receptors; those are even smaller to actually visualize,” she said. “But we have technologies where we can target those receptors with fluorophores. And then we can look at large areas very quickly.” Meanwhile, the ability of cancer cells to resist cell death and evade growth suppressors often results in thickening of epithelium throughout the body. “So, if we can measure the thickness of the epithelium, we can see that there’s something wrong with that tissue,” she said.

As for cancer’s propensity for invasion and metastasis, “here, we’re looking at how the collagen structure [between the cells] has changed and whether there’s layer breakdown or not. Optical imaging can detect cancer. However, high resolution optical techniques can only image about 1 mm deep, so unless you’re looking at the skin or the eye, you’re going to have to develop an endoscope to be able to view these hallmarks.”

OCT images the tissue microstructure, generally in a resolution of 2-20 microns, at a depth of 1-2 mm, and it measures reflected light. When possible, Dr. Barton combines OCT with laser-induced fluorescence for enhanced accuracy of detection of cancer. Induced fluorescence senses molecular information with the natural fluorophores in the body or with targeted exogenous agents. Then there’s multiphoton microscopy, an advanced imaging technique that enables clinicians to view cellular and subcellular events within living tissue. Early models of this technology “took up entire benches” in physics labs, Dr. Barton said, but she and other investigators are designing smaller devices for use in clinics. “This is exciting, because not only do we [view] subcellular structure with this modality, but it can also be highly sensitive to collagen structure,” she said.
 

Ovarian cancer model

In a model of ovarian cancer, she and colleagues externalized the ovaries of a mouse, imaged the organs, put them back in, and reassessed them at 8 weeks. “This model develops cancer very quickly,” said Dr. Barton, who once worked for McDonnell Douglas on the Space Station program. At 8 weeks, using fluorescence and targeted agents with a tabletop multiphoton microscopy system, they observed that the proliferation signals of cancer had begun. “So, with an agent targeted to the folate receptor or to other receptors that are implicated in cancer development, we can see that ovaries and fallopian tubes are lighting up,” she said.

With proof of concept established with the mouse study, she and other researchers are drawing from technological advances to create tiny laser systems for use in the clinic to image a variety of structures in the human body. Optics advances include bulk optics and all-fiber designs where engineers can create an imaging probe that’s only 125 microns in diameter, “or maybe even as small as 70 microns in diameter,” she said. “We can do fabrications on the tips of endoscopes to redirect the light and focus it. We can also do 3-D printing and spiral scanning to create miniature devices to make new advances. That means that instead of just white light imaging of the colon or the lung like we have had in the past, we can start moving into smaller structures, such as the eustachian tube, the fallopian tube, the bile ducts, or making miniature devices for brain biopsies, lung biopsies, and maybe being able to get into bronchioles and arterioles.”

According to Dr. Barton, prior research has demonstrated that cerebral vasculature can be imaged with a catheter 400 microns in diameter, the spaces in the lungs can be imaged with a needle that is 310 microns in diameter, and the inner structures of the eustachian tube can be viewed with an endoscope 1 mm in diameter.

She and her colleagues are developing an OCT/fluorescence imaging falloposcope that is 0.8 mm in diameter, flexible, and steerable, as a tool for early detection of ovarian cancer in humans. “It’s now known that most ovarian cancer starts in the fallopian tubes,” Dr. Barton said. “It’s metastatic disease when those cells break off from the fallopian tubes and go to the ovaries. We wanted to create an imaging system where we created a fiber bundle that we could navigate with white light and with fluorescence so that we can see these early stages of cancer [and] how they fluoresce differently. We also wanted to have an OCT system so that we could image through the wall of the fallopian tube and look for that layer thickening and other precursors to ovarian cancer.”

To date, in vivo testing in healthy women has demonstrated that the miniature endoscope is able to reach the fallopian tubes through the natural orifice of the vagina and uterus. “That is pretty exciting,” she said. “The images may not be of the highest quality, but we are advancing.”

Dr. Barton reported having no relevant financial disclosures.

PHOENIX – The way Jennifer Barton, PhD, sees it, optical coherence tomography (OCT), laser-induced fluorescence, and multiphoton microscopy are poised to revolutionize the future of cancer detection.

Chris Richards/University of Arizona

In a lecture during a multispecialty roundup of cutting-edge energy-based device applications at the annual conference of the American Society for Laser Medicine and Surgery, Dr. Barton, a biomedical engineer who directs the BIO5 Institute at the University of Arizona, Tucson, said that while no current modality exists to enable physicians in dermatology and other specialties to view internal structures throughout the entire body with cellular resolution, refining existing technologies is a good way to start.

In 2011, renowned cancer researchers Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, proposed six hallmarks of cancer, which include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Each hallmark poses unique imaging challenges. For example, enabling replicative immortality “means that the cell nuclei change size and shape; they change their position,” said Dr. Barton, who is also professor of biomedical engineering and optical sciences at the university. “If we want to see that, we’re going to need an imaging modality that’s subcellular in resolution.”

Similarly, if clinicians want to view how proliferative signaling is changing, “that means being able to visualize the cell surface receptors; those are even smaller to actually visualize,” she said. “But we have technologies where we can target those receptors with fluorophores. And then we can look at large areas very quickly.” Meanwhile, the ability of cancer cells to resist cell death and evade growth suppressors often results in thickening of epithelium throughout the body. “So, if we can measure the thickness of the epithelium, we can see that there’s something wrong with that tissue,” she said.

As for cancer’s propensity for invasion and metastasis, “here, we’re looking at how the collagen structure [between the cells] has changed and whether there’s layer breakdown or not. Optical imaging can detect cancer. However, high resolution optical techniques can only image about 1 mm deep, so unless you’re looking at the skin or the eye, you’re going to have to develop an endoscope to be able to view these hallmarks.”

OCT images the tissue microstructure, generally in a resolution of 2-20 microns, at a depth of 1-2 mm, and it measures reflected light. When possible, Dr. Barton combines OCT with laser-induced fluorescence for enhanced accuracy of detection of cancer. Induced fluorescence senses molecular information with the natural fluorophores in the body or with targeted exogenous agents. Then there’s multiphoton microscopy, an advanced imaging technique that enables clinicians to view cellular and subcellular events within living tissue. Early models of this technology “took up entire benches” in physics labs, Dr. Barton said, but she and other investigators are designing smaller devices for use in clinics. “This is exciting, because not only do we [view] subcellular structure with this modality, but it can also be highly sensitive to collagen structure,” she said.
 

Ovarian cancer model

In a model of ovarian cancer, she and colleagues externalized the ovaries of a mouse, imaged the organs, put them back in, and reassessed them at 8 weeks. “This model develops cancer very quickly,” said Dr. Barton, who once worked for McDonnell Douglas on the Space Station program. At 8 weeks, using fluorescence and targeted agents with a tabletop multiphoton microscopy system, they observed that the proliferation signals of cancer had begun. “So, with an agent targeted to the folate receptor or to other receptors that are implicated in cancer development, we can see that ovaries and fallopian tubes are lighting up,” she said.

With proof of concept established with the mouse study, she and other researchers are drawing from technological advances to create tiny laser systems for use in the clinic to image a variety of structures in the human body. Optics advances include bulk optics and all-fiber designs where engineers can create an imaging probe that’s only 125 microns in diameter, “or maybe even as small as 70 microns in diameter,” she said. “We can do fabrications on the tips of endoscopes to redirect the light and focus it. We can also do 3-D printing and spiral scanning to create miniature devices to make new advances. That means that instead of just white light imaging of the colon or the lung like we have had in the past, we can start moving into smaller structures, such as the eustachian tube, the fallopian tube, the bile ducts, or making miniature devices for brain biopsies, lung biopsies, and maybe being able to get into bronchioles and arterioles.”

According to Dr. Barton, prior research has demonstrated that cerebral vasculature can be imaged with a catheter 400 microns in diameter, the spaces in the lungs can be imaged with a needle that is 310 microns in diameter, and the inner structures of the eustachian tube can be viewed with an endoscope 1 mm in diameter.

She and her colleagues are developing an OCT/fluorescence imaging falloposcope that is 0.8 mm in diameter, flexible, and steerable, as a tool for early detection of ovarian cancer in humans. “It’s now known that most ovarian cancer starts in the fallopian tubes,” Dr. Barton said. “It’s metastatic disease when those cells break off from the fallopian tubes and go to the ovaries. We wanted to create an imaging system where we created a fiber bundle that we could navigate with white light and with fluorescence so that we can see these early stages of cancer [and] how they fluoresce differently. We also wanted to have an OCT system so that we could image through the wall of the fallopian tube and look for that layer thickening and other precursors to ovarian cancer.”

To date, in vivo testing in healthy women has demonstrated that the miniature endoscope is able to reach the fallopian tubes through the natural orifice of the vagina and uterus. “That is pretty exciting,” she said. “The images may not be of the highest quality, but we are advancing.”

Dr. Barton reported having no relevant financial disclosures.