Pharmacology

PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.

In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).

Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published  in the Journal of the American College of Cardiology.

Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
 

PCSK9 inhibitors as anti-inflammatories

Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.

The study adds to “our clinical arsenal against COVID-19,” and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.

The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.

Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”

If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.

In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.

But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
 

A single injection

The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.  

They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.

Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.

Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.

The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.

Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).

A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.

Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”

Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.

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

PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.

In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).

Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published  in the Journal of the American College of Cardiology.

Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
 

PCSK9 inhibitors as anti-inflammatories

Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.

The study adds to “our clinical arsenal against COVID-19,” and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.

The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.

Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”

If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.

In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.

But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
 

A single injection

The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.  

They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.

Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.

Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.

The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.

Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).

A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.

Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”

Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.

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

PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.

In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).

Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published  in the Journal of the American College of Cardiology.

Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
 

PCSK9 inhibitors as anti-inflammatories

Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.

The study adds to “our clinical arsenal against COVID-19,” and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.

The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.

Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”

If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.

In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.

But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
 

A single injection

The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.  

They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.

Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.

Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.

The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.

Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).

A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.

Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”

Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.

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

The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
 

Olivier Le Moal/Getty Images

The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m².

Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m²).

In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.

In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.

“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.

Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.

Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.

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

The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
 

Olivier Le Moal/Getty Images

The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m².

Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m²).

In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.

In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.

“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.

Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.

Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.

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

The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
 

Olivier Le Moal/Getty Images

The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m².

Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m²).

In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.

In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.

“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.

Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.

Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.

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

Adding venetoclax to ibrutinib for chronic lymphocytic leukemia (CLL) improved rates of durable, treatment-free remission among 45 patients at the University of Texas MD Anderson Cancer Center, Houston.

Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.

Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.

“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.

However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
 

Complete remission in over half

The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.

Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.

On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.

The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.

Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.

“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.

There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.

The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.

No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.

The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.

Adding venetoclax to ibrutinib for chronic lymphocytic leukemia (CLL) improved rates of durable, treatment-free remission among 45 patients at the University of Texas MD Anderson Cancer Center, Houston.

Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.

Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.

“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.

However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
 

Complete remission in over half

The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.

Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.

On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.

The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.

Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.

“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.

There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.

The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.

No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.

The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.

Adding venetoclax to ibrutinib for chronic lymphocytic leukemia (CLL) improved rates of durable, treatment-free remission among 45 patients at the University of Texas MD Anderson Cancer Center, Houston.

Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.

Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.

“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.

However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
 

Complete remission in over half

The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.

Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.

On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.

The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.

Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.

“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.

There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.

The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.

No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.

The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.

Cancer dietitian Lisa Cianciotta often finds herself sitting across from a patient who suddenly fishes a bottle of antioxidant supplements from their bag and says, “My friend told me this works really well,” or “I read on the Internet that this is supposed to be really good for cancer.” 

Although taking an antioxidant pill sounds harmless, Ms. Cianciotta, a clinical dietitian who works with cancer patients at New York–Presbyterian Hospital, knows well that this popular dietary supplement can interfere with a patient’s radiation or chemotherapy.

But many patients with cancer believe these over-the-counter vitamins, minerals, or herbal remedies will help them, and most use at least one dietary supplement alongside their cancer treatment.

And that leaves Ms. Cianciotta with a delicate conversation ahead of her. 

Drug-supplement interactions are complex, often varying by supplement, cancer, and treatment type, and can do more harm than good. Popular dietary supplements may, for instance, cancel the effects of a cancer treatment, making it less effective, or increase serious side effects, such as liver toxicity. But in other cases, supplementation, such as vitamin D for patients who lack the vitamin, may be beneficial, Ms. Cianciotta said. 

These drug-supplement interactions can be hard to pinpoint, given that more than two-thirds of doctors don’t know their patients are using supplements.

Here’s what patients need to know about the potential risks of supplement use during treatment, and how oncologists can address this thorny, often poorly understood topic with patients.
 

The complex drug-supplement landscape

The list of dietary supplements and how they can interact with different treatments and cancer types is long and nuanced. 

But certain supplements appear to affect cancer treatments regardless of other things and should be avoided. Any supplement that strongly alters the body’s levels of the protein cytochromes P450 is one example. This group of enzymes plays a key role in metabolizing drugs, including chemotherapy and immunotherapy agents. 

Certain supplements – most notably St. John’s wort extract – may decrease or increase the activity of cytochrome P450, which can then  affect the concentrations of anticancer drugs in the blood, said William Figg, PharmD, an associate director of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md. Studies show, for instance, that this common herbal supplement can increase the activity of cytochrome P450, resulting in lower levels of cancer drugs.

Outside of drug metabolism, patients with hormone-related cancers, such as breast and prostate cancers, should steer clear of dietary supplements that can alter levels of testosterone or estrogen, Dr. Figg said. The evergreen shrub ashwagandha, for example, is marketed to reduce stress and fatigue, but can also increase testosterone levels – a potential problem for those with prostate cancer receiving androgen deprivation therapy, which lowers testosterone levels. 

Many oncologists counsel patients against using antioxidant-based dietary supplements – particularly turmeric and green tea extract – while they have radiation therapy and certain chemotherapies. These therapies work by creating an abundance of highly reactive molecules called free radicals in tumor cells, which increase stress within these cells, ultimately killing them off. Antioxidants, in theory, can neutralize this effect, said Skyler Johnson, MD, a radiation oncologist at Huntsman Cancer Institute at the University of Utah, Salt Lake City.  Some studies suggest that antioxidant supplements may lessen the effects of radiation and chemotherapy, although the evidence is mixed.

Some dietary supplements, including high-dose green tea extract and vitamin A, can cause kidney or liver toxicity, and “many cancer patients already have compromised kidney or liver function,” said Jun J. Mao, MD, chief of integrative medicine at Memorial Sloan Kettering Cancer Center in New York. Even herbs that don’t interfere with how well a cancer drug works, such as stevia, can increase treatment-related side effects, such as nausea and vomiting. 

Another potential problem with dietary supplements: It’s nearly impossible to know exactly what’s in them. For instance, just last year, the Food and Drug Administration sent nearly 50 warning letters to companies marketing dietary supplements. The issue is that federal regulations governing production are less strict for supplements than for medications. As a result, some supplements contain ingredients not listed on the label. 

One historical example was the supplement PC-SPES, a mix of eight herbs, marketed to men with prostate cancer. The supplement was recalled in 2002 after certain batches were found to contain traces of prescription drugs, including diethylstilbestrol, ethinyl estradiol, warfarin, and alprazolam.

To further complicate matters, some dietary supplements can be helpful. Most patients with cancer “are malnourished and missing out on nutrients they could be getting from food,” said Ms. Cianciotta.

Patients are tested routinely for vitamin deficiencies and receive supplements as needed, she said. Vitamin D and folic acid are two of the most common deficiencies in this patient population. Vitamin D supplementation can improve outcomes in patients who have received a stem cell transplant by aiding engraftment and rebuilding the immune system, while folic acid supplementation can help to raise low red blood cell counts and hemoglobin levels. 

Although she rarely sees vitamin toxicity, Ms. Cianciotta stressed that more is not always better and supplement use, even when it seems safe or warranted due to a deficiency, should be taken under supervision, and monitored carefully by the patient’s care team. 
 

Bringing supplement use into the light

Too often, providers are unaware of a patient’s supplement use. 

A core reason: Dietary supplements are often touted as natural, which many patients equate with safety, said Samantha Heller, a senior clinical nutritionist at New York (N.Y.) University Langone Health. 

That means patients may not know a supplement can act like a drug and interfere with their cancer treatment, and thus may not see the importance of telling their doctors.

Still, the promise of herbs, vitamins, and minerals can be alluring, and there are many reasons patients decide to partake. One major appeal: Dietary supplements can help some patients feel empowered.

“Cancer is a disease that takes away a lot of control from the individual. Taking supplements or herbs is a way to regain some sense of control,” said Dr. Mao. 

The phenomenon can also be cultural, he said. Some people grow up taking herbs and supplements to stay healthy or combat health woes.

Pressure or advice from family or friends who may think they are helping a loved one with their dietary recommendations may play a role as well. Friends and family “cannot prescribe chemo, but they can buy herbs and supplements,” Dr. Mao said. 

Patients seeking greater control over their health or who feel high levels of anxiety may be more likely to take suggestions from friends and family or more likely to believe false or misleading claims about the efficacy or safety of supplements, explained  medical oncologist William Dahut, MD, chief scientific officer for the American Cancer Society. 

Plus, social media often amplifies and normalizes this misinformation, noted Dr. Johnson. In a 2021 study published in the Journal of the National Cancer Institute, he and colleagues found that one-third of the most popular articles on cancer treatment posted to social media in 2018 and 2019 contained false, inaccurate, or misleading information that was often harmful. 

Some of the false claims centered on unproven, potentially unsafe herbal remedies, according to Dr. Johnson. These included “lung cancer can be cured with cannabis oil” and “golden berries cure and prevent cancer.” 

Given exaggerated claims of “cures,” some patients may keep their supplement use under the radar out of fear they will be judged or criticized. 

“Clinicians should avoid making patients feel judged or telling people not to go online to do their own research,” Dr. Johnson said.

Guiding patients, instead, to accurate sources of online information may be one way to help patients feel empowered, he said. Cancer.gov and the Memorial Sloan Kettering Cancer Center’s About Herbs database provide accessible and accurate information on dietary supplements and cancer treatment for both health care professionals and patients, he noted. 

If a particular supplement is not safe during treatment, providers should be able to explain why, said  Ms. Cianciotta. In a recent study, 80% of health care providers surveyed believed that interactions between herbals and medications could be problematic, but only 15% could explain why. 

“Being able to explain why we are discouraging a particular supplement right now tends to be much better received than just telling a patient not to take something, because it is bad,” she said. 

Another key is listening closely to patients to understand why they may be taking a particular supplement. Does the patient feel out of control? Is nausea a problem? 

“Allowing patients to tell you why they are using a particular supplement will often reveal unmet needs or psychosocial challenges,” Dr. Mao said. This information can allow providers to suggest an evidence-based alternative, such as mindfulness meditation or acupuncture, to manage stress.

And if a patient has received a dietary supplement from well-meaning family and friends?

“Simply telling a patient that a given supplement is useless or harmful could create family tension,” said  Dr. Mao. 

Instead, he recommends reframing the issue. 

“We want to have a better understanding of how patients are tolerating chemo or immunotherapy before throwing other things on top of it. Let them know that now may just not be the right time to add a supplement to the mix,” Dr. Mao said. 

The bottom line: “Patients want to play an active role in their own care, and we want to help them do that in a safe way,” he said. 

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

Cancer dietitian Lisa Cianciotta often finds herself sitting across from a patient who suddenly fishes a bottle of antioxidant supplements from their bag and says, “My friend told me this works really well,” or “I read on the Internet that this is supposed to be really good for cancer.” 

Although taking an antioxidant pill sounds harmless, Ms. Cianciotta, a clinical dietitian who works with cancer patients at New York–Presbyterian Hospital, knows well that this popular dietary supplement can interfere with a patient’s radiation or chemotherapy.

But many patients with cancer believe these over-the-counter vitamins, minerals, or herbal remedies will help them, and most use at least one dietary supplement alongside their cancer treatment.

And that leaves Ms. Cianciotta with a delicate conversation ahead of her. 

Drug-supplement interactions are complex, often varying by supplement, cancer, and treatment type, and can do more harm than good. Popular dietary supplements may, for instance, cancel the effects of a cancer treatment, making it less effective, or increase serious side effects, such as liver toxicity. But in other cases, supplementation, such as vitamin D for patients who lack the vitamin, may be beneficial, Ms. Cianciotta said. 

These drug-supplement interactions can be hard to pinpoint, given that more than two-thirds of doctors don’t know their patients are using supplements.

Here’s what patients need to know about the potential risks of supplement use during treatment, and how oncologists can address this thorny, often poorly understood topic with patients.
 

The complex drug-supplement landscape

The list of dietary supplements and how they can interact with different treatments and cancer types is long and nuanced. 

But certain supplements appear to affect cancer treatments regardless of other things and should be avoided. Any supplement that strongly alters the body’s levels of the protein cytochromes P450 is one example. This group of enzymes plays a key role in metabolizing drugs, including chemotherapy and immunotherapy agents. 

Certain supplements – most notably St. John’s wort extract – may decrease or increase the activity of cytochrome P450, which can then  affect the concentrations of anticancer drugs in the blood, said William Figg, PharmD, an associate director of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md. Studies show, for instance, that this common herbal supplement can increase the activity of cytochrome P450, resulting in lower levels of cancer drugs.

Outside of drug metabolism, patients with hormone-related cancers, such as breast and prostate cancers, should steer clear of dietary supplements that can alter levels of testosterone or estrogen, Dr. Figg said. The evergreen shrub ashwagandha, for example, is marketed to reduce stress and fatigue, but can also increase testosterone levels – a potential problem for those with prostate cancer receiving androgen deprivation therapy, which lowers testosterone levels. 

Many oncologists counsel patients against using antioxidant-based dietary supplements – particularly turmeric and green tea extract – while they have radiation therapy and certain chemotherapies. These therapies work by creating an abundance of highly reactive molecules called free radicals in tumor cells, which increase stress within these cells, ultimately killing them off. Antioxidants, in theory, can neutralize this effect, said Skyler Johnson, MD, a radiation oncologist at Huntsman Cancer Institute at the University of Utah, Salt Lake City.  Some studies suggest that antioxidant supplements may lessen the effects of radiation and chemotherapy, although the evidence is mixed.

Some dietary supplements, including high-dose green tea extract and vitamin A, can cause kidney or liver toxicity, and “many cancer patients already have compromised kidney or liver function,” said Jun J. Mao, MD, chief of integrative medicine at Memorial Sloan Kettering Cancer Center in New York. Even herbs that don’t interfere with how well a cancer drug works, such as stevia, can increase treatment-related side effects, such as nausea and vomiting. 

Another potential problem with dietary supplements: It’s nearly impossible to know exactly what’s in them. For instance, just last year, the Food and Drug Administration sent nearly 50 warning letters to companies marketing dietary supplements. The issue is that federal regulations governing production are less strict for supplements than for medications. As a result, some supplements contain ingredients not listed on the label. 

One historical example was the supplement PC-SPES, a mix of eight herbs, marketed to men with prostate cancer. The supplement was recalled in 2002 after certain batches were found to contain traces of prescription drugs, including diethylstilbestrol, ethinyl estradiol, warfarin, and alprazolam.

To further complicate matters, some dietary supplements can be helpful. Most patients with cancer “are malnourished and missing out on nutrients they could be getting from food,” said Ms. Cianciotta.

Patients are tested routinely for vitamin deficiencies and receive supplements as needed, she said. Vitamin D and folic acid are two of the most common deficiencies in this patient population. Vitamin D supplementation can improve outcomes in patients who have received a stem cell transplant by aiding engraftment and rebuilding the immune system, while folic acid supplementation can help to raise low red blood cell counts and hemoglobin levels. 

Although she rarely sees vitamin toxicity, Ms. Cianciotta stressed that more is not always better and supplement use, even when it seems safe or warranted due to a deficiency, should be taken under supervision, and monitored carefully by the patient’s care team. 
 

Bringing supplement use into the light

Too often, providers are unaware of a patient’s supplement use. 

A core reason: Dietary supplements are often touted as natural, which many patients equate with safety, said Samantha Heller, a senior clinical nutritionist at New York (N.Y.) University Langone Health. 

That means patients may not know a supplement can act like a drug and interfere with their cancer treatment, and thus may not see the importance of telling their doctors.

Still, the promise of herbs, vitamins, and minerals can be alluring, and there are many reasons patients decide to partake. One major appeal: Dietary supplements can help some patients feel empowered.

“Cancer is a disease that takes away a lot of control from the individual. Taking supplements or herbs is a way to regain some sense of control,” said Dr. Mao. 

The phenomenon can also be cultural, he said. Some people grow up taking herbs and supplements to stay healthy or combat health woes.

Pressure or advice from family or friends who may think they are helping a loved one with their dietary recommendations may play a role as well. Friends and family “cannot prescribe chemo, but they can buy herbs and supplements,” Dr. Mao said. 

Patients seeking greater control over their health or who feel high levels of anxiety may be more likely to take suggestions from friends and family or more likely to believe false or misleading claims about the efficacy or safety of supplements, explained  medical oncologist William Dahut, MD, chief scientific officer for the American Cancer Society. 

Plus, social media often amplifies and normalizes this misinformation, noted Dr. Johnson. In a 2021 study published in the Journal of the National Cancer Institute, he and colleagues found that one-third of the most popular articles on cancer treatment posted to social media in 2018 and 2019 contained false, inaccurate, or misleading information that was often harmful. 

Some of the false claims centered on unproven, potentially unsafe herbal remedies, according to Dr. Johnson. These included “lung cancer can be cured with cannabis oil” and “golden berries cure and prevent cancer.” 

Given exaggerated claims of “cures,” some patients may keep their supplement use under the radar out of fear they will be judged or criticized. 

“Clinicians should avoid making patients feel judged or telling people not to go online to do their own research,” Dr. Johnson said.

Guiding patients, instead, to accurate sources of online information may be one way to help patients feel empowered, he said. Cancer.gov and the Memorial Sloan Kettering Cancer Center’s About Herbs database provide accessible and accurate information on dietary supplements and cancer treatment for both health care professionals and patients, he noted. 

If a particular supplement is not safe during treatment, providers should be able to explain why, said  Ms. Cianciotta. In a recent study, 80% of health care providers surveyed believed that interactions between herbals and medications could be problematic, but only 15% could explain why. 

“Being able to explain why we are discouraging a particular supplement right now tends to be much better received than just telling a patient not to take something, because it is bad,” she said. 

Another key is listening closely to patients to understand why they may be taking a particular supplement. Does the patient feel out of control? Is nausea a problem? 

“Allowing patients to tell you why they are using a particular supplement will often reveal unmet needs or psychosocial challenges,” Dr. Mao said. This information can allow providers to suggest an evidence-based alternative, such as mindfulness meditation or acupuncture, to manage stress.

And if a patient has received a dietary supplement from well-meaning family and friends?

“Simply telling a patient that a given supplement is useless or harmful could create family tension,” said  Dr. Mao. 

Instead, he recommends reframing the issue. 

“We want to have a better understanding of how patients are tolerating chemo or immunotherapy before throwing other things on top of it. Let them know that now may just not be the right time to add a supplement to the mix,” Dr. Mao said. 

The bottom line: “Patients want to play an active role in their own care, and we want to help them do that in a safe way,” he said. 

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

Cancer dietitian Lisa Cianciotta often finds herself sitting across from a patient who suddenly fishes a bottle of antioxidant supplements from their bag and says, “My friend told me this works really well,” or “I read on the Internet that this is supposed to be really good for cancer.” 

Although taking an antioxidant pill sounds harmless, Ms. Cianciotta, a clinical dietitian who works with cancer patients at New York–Presbyterian Hospital, knows well that this popular dietary supplement can interfere with a patient’s radiation or chemotherapy.

But many patients with cancer believe these over-the-counter vitamins, minerals, or herbal remedies will help them, and most use at least one dietary supplement alongside their cancer treatment.

And that leaves Ms. Cianciotta with a delicate conversation ahead of her. 

Drug-supplement interactions are complex, often varying by supplement, cancer, and treatment type, and can do more harm than good. Popular dietary supplements may, for instance, cancel the effects of a cancer treatment, making it less effective, or increase serious side effects, such as liver toxicity. But in other cases, supplementation, such as vitamin D for patients who lack the vitamin, may be beneficial, Ms. Cianciotta said. 

These drug-supplement interactions can be hard to pinpoint, given that more than two-thirds of doctors don’t know their patients are using supplements.

Here’s what patients need to know about the potential risks of supplement use during treatment, and how oncologists can address this thorny, often poorly understood topic with patients.
 

The complex drug-supplement landscape

The list of dietary supplements and how they can interact with different treatments and cancer types is long and nuanced. 

But certain supplements appear to affect cancer treatments regardless of other things and should be avoided. Any supplement that strongly alters the body’s levels of the protein cytochromes P450 is one example. This group of enzymes plays a key role in metabolizing drugs, including chemotherapy and immunotherapy agents. 

Certain supplements – most notably St. John’s wort extract – may decrease or increase the activity of cytochrome P450, which can then  affect the concentrations of anticancer drugs in the blood, said William Figg, PharmD, an associate director of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md. Studies show, for instance, that this common herbal supplement can increase the activity of cytochrome P450, resulting in lower levels of cancer drugs.

Outside of drug metabolism, patients with hormone-related cancers, such as breast and prostate cancers, should steer clear of dietary supplements that can alter levels of testosterone or estrogen, Dr. Figg said. The evergreen shrub ashwagandha, for example, is marketed to reduce stress and fatigue, but can also increase testosterone levels – a potential problem for those with prostate cancer receiving androgen deprivation therapy, which lowers testosterone levels. 

Many oncologists counsel patients against using antioxidant-based dietary supplements – particularly turmeric and green tea extract – while they have radiation therapy and certain chemotherapies. These therapies work by creating an abundance of highly reactive molecules called free radicals in tumor cells, which increase stress within these cells, ultimately killing them off. Antioxidants, in theory, can neutralize this effect, said Skyler Johnson, MD, a radiation oncologist at Huntsman Cancer Institute at the University of Utah, Salt Lake City.  Some studies suggest that antioxidant supplements may lessen the effects of radiation and chemotherapy, although the evidence is mixed.

Some dietary supplements, including high-dose green tea extract and vitamin A, can cause kidney or liver toxicity, and “many cancer patients already have compromised kidney or liver function,” said Jun J. Mao, MD, chief of integrative medicine at Memorial Sloan Kettering Cancer Center in New York. Even herbs that don’t interfere with how well a cancer drug works, such as stevia, can increase treatment-related side effects, such as nausea and vomiting. 

Another potential problem with dietary supplements: It’s nearly impossible to know exactly what’s in them. For instance, just last year, the Food and Drug Administration sent nearly 50 warning letters to companies marketing dietary supplements. The issue is that federal regulations governing production are less strict for supplements than for medications. As a result, some supplements contain ingredients not listed on the label. 

One historical example was the supplement PC-SPES, a mix of eight herbs, marketed to men with prostate cancer. The supplement was recalled in 2002 after certain batches were found to contain traces of prescription drugs, including diethylstilbestrol, ethinyl estradiol, warfarin, and alprazolam.

To further complicate matters, some dietary supplements can be helpful. Most patients with cancer “are malnourished and missing out on nutrients they could be getting from food,” said Ms. Cianciotta.

Patients are tested routinely for vitamin deficiencies and receive supplements as needed, she said. Vitamin D and folic acid are two of the most common deficiencies in this patient population. Vitamin D supplementation can improve outcomes in patients who have received a stem cell transplant by aiding engraftment and rebuilding the immune system, while folic acid supplementation can help to raise low red blood cell counts and hemoglobin levels. 

Although she rarely sees vitamin toxicity, Ms. Cianciotta stressed that more is not always better and supplement use, even when it seems safe or warranted due to a deficiency, should be taken under supervision, and monitored carefully by the patient’s care team. 
 

Bringing supplement use into the light

Too often, providers are unaware of a patient’s supplement use. 

A core reason: Dietary supplements are often touted as natural, which many patients equate with safety, said Samantha Heller, a senior clinical nutritionist at New York (N.Y.) University Langone Health. 

That means patients may not know a supplement can act like a drug and interfere with their cancer treatment, and thus may not see the importance of telling their doctors.

Still, the promise of herbs, vitamins, and minerals can be alluring, and there are many reasons patients decide to partake. One major appeal: Dietary supplements can help some patients feel empowered.

“Cancer is a disease that takes away a lot of control from the individual. Taking supplements or herbs is a way to regain some sense of control,” said Dr. Mao. 

The phenomenon can also be cultural, he said. Some people grow up taking herbs and supplements to stay healthy or combat health woes.

Pressure or advice from family or friends who may think they are helping a loved one with their dietary recommendations may play a role as well. Friends and family “cannot prescribe chemo, but they can buy herbs and supplements,” Dr. Mao said. 

Patients seeking greater control over their health or who feel high levels of anxiety may be more likely to take suggestions from friends and family or more likely to believe false or misleading claims about the efficacy or safety of supplements, explained  medical oncologist William Dahut, MD, chief scientific officer for the American Cancer Society. 

Plus, social media often amplifies and normalizes this misinformation, noted Dr. Johnson. In a 2021 study published in the Journal of the National Cancer Institute, he and colleagues found that one-third of the most popular articles on cancer treatment posted to social media in 2018 and 2019 contained false, inaccurate, or misleading information that was often harmful. 

Some of the false claims centered on unproven, potentially unsafe herbal remedies, according to Dr. Johnson. These included “lung cancer can be cured with cannabis oil” and “golden berries cure and prevent cancer.” 

Given exaggerated claims of “cures,” some patients may keep their supplement use under the radar out of fear they will be judged or criticized. 

“Clinicians should avoid making patients feel judged or telling people not to go online to do their own research,” Dr. Johnson said.

Guiding patients, instead, to accurate sources of online information may be one way to help patients feel empowered, he said. Cancer.gov and the Memorial Sloan Kettering Cancer Center’s About Herbs database provide accessible and accurate information on dietary supplements and cancer treatment for both health care professionals and patients, he noted. 

If a particular supplement is not safe during treatment, providers should be able to explain why, said  Ms. Cianciotta. In a recent study, 80% of health care providers surveyed believed that interactions between herbals and medications could be problematic, but only 15% could explain why. 

“Being able to explain why we are discouraging a particular supplement right now tends to be much better received than just telling a patient not to take something, because it is bad,” she said. 

Another key is listening closely to patients to understand why they may be taking a particular supplement. Does the patient feel out of control? Is nausea a problem? 

“Allowing patients to tell you why they are using a particular supplement will often reveal unmet needs or psychosocial challenges,” Dr. Mao said. This information can allow providers to suggest an evidence-based alternative, such as mindfulness meditation or acupuncture, to manage stress.

And if a patient has received a dietary supplement from well-meaning family and friends?

“Simply telling a patient that a given supplement is useless or harmful could create family tension,” said  Dr. Mao. 

Instead, he recommends reframing the issue. 

“We want to have a better understanding of how patients are tolerating chemo or immunotherapy before throwing other things on top of it. Let them know that now may just not be the right time to add a supplement to the mix,” Dr. Mao said. 

The bottom line: “Patients want to play an active role in their own care, and we want to help them do that in a safe way,” he said. 

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

A combination of HER2-targeted drugs used in breast cancer is now available for use in colorectal cancer.

The U.S. Food and Drug Administration has granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for use in RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed after fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy.

This is the first FDA-approved treatment for HER2-positive metastatic colorectal cancer, maker Seagen said in a Jan. 19 press release.

“Historically, patients with HER2-positive metastatic colorectal cancer who have progressed following frontline therapy have had poor outcomes. The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients,” John Strickler, MD, associate professor of medicine at Duke University Medical Center, Durham, N.C., said in the press release.

Dr. Strickler was the lead investigator on the approval trial, dubbed MOUNTAINEER, which involved 84 patients who met the treatment criteria and who had also been treated with an anti-VEGF antibody. Participants whose tumors were deficient in mismatch repair proteins or were microsatellite instability–high must also have received a PD-1 inhibitor. Patients who received prior anti-HER2 therapy were excluded, the FDA explained in its own press release.

Participants were treated with tucatinib 300 mg orally twice daily– the recommended dose in product labeling – with trastuzumab administered at a loading dose of 8 mg/kg intravenously on day 1 of cycle 1 followed by a maintenance dose of trastuzumab 6 mg/kg on day 1 of each subsequent 21-day cycle.

Overall response rate was 38%, and median duration of response was 12.4 months.

The most common adverse events, occurring in at least 20% of study participants, were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities were increased creatinine, decreased lymphocytes, increased alanine aminotransferase, and decreased hemoglobin, among others.

Serious adverse reactions occurred in 22% of patients. The most common (occurring in ≥ 2% of patients) were intestinal obstruction (7%); urinary tract infection (3.5%); and pneumonia, abdominal pain, and rectal perforation (2.3% each). Adverse reactions leading to permanent discontinuation occurred in 6% of patients, including increased alanine aminotransferase in 2.3%.

Continued approval for the indication may be contingent upon verification and description of clinical benefit in confirmatory trials, the company said.

A global, randomized phase 3 clinical trial (MOUNTAINEER-03) is ongoing and is comparing tucatinib in combination with trastuzumab and mFOLFOX6 with standard of care and is intended to serve as a confirmatory trial, the company said.

Tucatinib is already approved in combination with trastuzumab and capecitabine for use in the treatment of advanced unresectable or metastatic HER2-positive breast cancer.

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

A combination of HER2-targeted drugs used in breast cancer is now available for use in colorectal cancer.

The U.S. Food and Drug Administration has granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for use in RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed after fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy.

This is the first FDA-approved treatment for HER2-positive metastatic colorectal cancer, maker Seagen said in a Jan. 19 press release.

“Historically, patients with HER2-positive metastatic colorectal cancer who have progressed following frontline therapy have had poor outcomes. The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients,” John Strickler, MD, associate professor of medicine at Duke University Medical Center, Durham, N.C., said in the press release.

Dr. Strickler was the lead investigator on the approval trial, dubbed MOUNTAINEER, which involved 84 patients who met the treatment criteria and who had also been treated with an anti-VEGF antibody. Participants whose tumors were deficient in mismatch repair proteins or were microsatellite instability–high must also have received a PD-1 inhibitor. Patients who received prior anti-HER2 therapy were excluded, the FDA explained in its own press release.

Participants were treated with tucatinib 300 mg orally twice daily– the recommended dose in product labeling – with trastuzumab administered at a loading dose of 8 mg/kg intravenously on day 1 of cycle 1 followed by a maintenance dose of trastuzumab 6 mg/kg on day 1 of each subsequent 21-day cycle.

Overall response rate was 38%, and median duration of response was 12.4 months.

The most common adverse events, occurring in at least 20% of study participants, were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities were increased creatinine, decreased lymphocytes, increased alanine aminotransferase, and decreased hemoglobin, among others.

Serious adverse reactions occurred in 22% of patients. The most common (occurring in ≥ 2% of patients) were intestinal obstruction (7%); urinary tract infection (3.5%); and pneumonia, abdominal pain, and rectal perforation (2.3% each). Adverse reactions leading to permanent discontinuation occurred in 6% of patients, including increased alanine aminotransferase in 2.3%.

Continued approval for the indication may be contingent upon verification and description of clinical benefit in confirmatory trials, the company said.

A global, randomized phase 3 clinical trial (MOUNTAINEER-03) is ongoing and is comparing tucatinib in combination with trastuzumab and mFOLFOX6 with standard of care and is intended to serve as a confirmatory trial, the company said.

Tucatinib is already approved in combination with trastuzumab and capecitabine for use in the treatment of advanced unresectable or metastatic HER2-positive breast cancer.

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

A combination of HER2-targeted drugs used in breast cancer is now available for use in colorectal cancer.

The U.S. Food and Drug Administration has granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for use in RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed after fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy.

This is the first FDA-approved treatment for HER2-positive metastatic colorectal cancer, maker Seagen said in a Jan. 19 press release.

“Historically, patients with HER2-positive metastatic colorectal cancer who have progressed following frontline therapy have had poor outcomes. The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients,” John Strickler, MD, associate professor of medicine at Duke University Medical Center, Durham, N.C., said in the press release.

Dr. Strickler was the lead investigator on the approval trial, dubbed MOUNTAINEER, which involved 84 patients who met the treatment criteria and who had also been treated with an anti-VEGF antibody. Participants whose tumors were deficient in mismatch repair proteins or were microsatellite instability–high must also have received a PD-1 inhibitor. Patients who received prior anti-HER2 therapy were excluded, the FDA explained in its own press release.

Participants were treated with tucatinib 300 mg orally twice daily– the recommended dose in product labeling – with trastuzumab administered at a loading dose of 8 mg/kg intravenously on day 1 of cycle 1 followed by a maintenance dose of trastuzumab 6 mg/kg on day 1 of each subsequent 21-day cycle.

Overall response rate was 38%, and median duration of response was 12.4 months.

The most common adverse events, occurring in at least 20% of study participants, were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities were increased creatinine, decreased lymphocytes, increased alanine aminotransferase, and decreased hemoglobin, among others.

Serious adverse reactions occurred in 22% of patients. The most common (occurring in ≥ 2% of patients) were intestinal obstruction (7%); urinary tract infection (3.5%); and pneumonia, abdominal pain, and rectal perforation (2.3% each). Adverse reactions leading to permanent discontinuation occurred in 6% of patients, including increased alanine aminotransferase in 2.3%.

Continued approval for the indication may be contingent upon verification and description of clinical benefit in confirmatory trials, the company said.

A global, randomized phase 3 clinical trial (MOUNTAINEER-03) is ongoing and is comparing tucatinib in combination with trastuzumab and mFOLFOX6 with standard of care and is intended to serve as a confirmatory trial, the company said.

Tucatinib is already approved in combination with trastuzumab and capecitabine for use in the treatment of advanced unresectable or metastatic HER2-positive breast cancer.

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

The only HIV vaccine nearing the completion of testing trials is not effective at preventing HIV, officials announced Wednesday.

The vaccine had been in development since 2019 and was given to 3,900 study participants through October 2022, but data shows it does not protect against HIV compared with a placebo, according to developer Janssen Pharmaceutical.

Experts estimate the failure means there won’t be another potential vaccine on the horizon for 3 to 5 years, the New York Times reported.

“It’s obviously disappointing,” Anthony Fauci, MD, former head of the National Institute of Allergy and Infectious Diseases, told MSNBC, noting that other areas of HIV treatment research are promising. “I don’t think that people should give up on the field of the HIV vaccine.”

No safety issues had been identified with the vaccine during the trial, which studied the experimental treatment in men who have sex with men or with transgender people.

There is no cure for HIV, but disease progression can be managed with existing treatments. HIV attacks the body’s immune system and destroys white blood cells, increasing the risk of other infections. More than 1.5 million people worldwide were infected with HIV in 2021 and 38.4 million people are living with the virus, according to UNAIDS.

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

The only HIV vaccine nearing the completion of testing trials is not effective at preventing HIV, officials announced Wednesday.

The vaccine had been in development since 2019 and was given to 3,900 study participants through October 2022, but data shows it does not protect against HIV compared with a placebo, according to developer Janssen Pharmaceutical.

Experts estimate the failure means there won’t be another potential vaccine on the horizon for 3 to 5 years, the New York Times reported.

“It’s obviously disappointing,” Anthony Fauci, MD, former head of the National Institute of Allergy and Infectious Diseases, told MSNBC, noting that other areas of HIV treatment research are promising. “I don’t think that people should give up on the field of the HIV vaccine.”

No safety issues had been identified with the vaccine during the trial, which studied the experimental treatment in men who have sex with men or with transgender people.

There is no cure for HIV, but disease progression can be managed with existing treatments. HIV attacks the body’s immune system and destroys white blood cells, increasing the risk of other infections. More than 1.5 million people worldwide were infected with HIV in 2021 and 38.4 million people are living with the virus, according to UNAIDS.

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

The only HIV vaccine nearing the completion of testing trials is not effective at preventing HIV, officials announced Wednesday.

The vaccine had been in development since 2019 and was given to 3,900 study participants through October 2022, but data shows it does not protect against HIV compared with a placebo, according to developer Janssen Pharmaceutical.

Experts estimate the failure means there won’t be another potential vaccine on the horizon for 3 to 5 years, the New York Times reported.

“It’s obviously disappointing,” Anthony Fauci, MD, former head of the National Institute of Allergy and Infectious Diseases, told MSNBC, noting that other areas of HIV treatment research are promising. “I don’t think that people should give up on the field of the HIV vaccine.”

No safety issues had been identified with the vaccine during the trial, which studied the experimental treatment in men who have sex with men or with transgender people.

There is no cure for HIV, but disease progression can be managed with existing treatments. HIV attacks the body’s immune system and destroys white blood cells, increasing the risk of other infections. More than 1.5 million people worldwide were infected with HIV in 2021 and 38.4 million people are living with the virus, according to UNAIDS.

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

A new study likely makes the best estimate yet of the degree of retinopathy risk that patients who take the antimalarial drug hydroxychloroquine (HCQ) can expect, deriving mainly from the cumulative dose taken during the first 5 years of use, according to a study published in Annals of Internal Medicine.

HCQ works to decrease activity in a patient’s immune system, which is effective in many cases of systemic lupus erythematosus, one of the most common indications for the drug. However, an adverse outcome of treatment can be HCQ retinopathy, a progressive form of vision loss in patients taking HCQ over an extended period (mostly for longer than 5 years). The disease is often asymptomatic, although some patients do present a paracentral scotoma and a decrease in color vision. Patients may also notice flashing shapes in their vision and find that they have difficulty reading. Eventually, HCQ retinopathy can lead to loss of visual acuity, loss of peripheral vision, and loss of night vision.

Researchers from Kaiser Permanente Northern California and Harvard Medical School analyzed 3,325 persons who received HCQ for 5 or more years between 2004 and 2020. Their goal was to both characterize the long-term risk for incident HCQ retinopathy and examine the degree to which average HCQ dose within the first 5 years of treatment serves as a prediction of the risk.

The researchers then estimated the risk for developing retinopathy after 15 years, according to patients’ average dosing levels during the first 5 years of therapy. Overall, 81 participants developed HCQ retinopathy with overall cumulative incidences of 2.5% after 10 years and 8.6% after 15 years; the risk was greater for those given a higher dose during the first 5 years of treatment.

The mechanism of how HCQ toxicity may occur is still not completely known. There is evidence that toxicity happens because HCQ binds to melanin in both the retinal pigment epithelium and uvea in high concentrations. HCQ can interfere with lysosomal function, leading to oxidation and accumulation of lysosomes, which can cause dysfunction of the retinal pigment epithelium.

Progressive retinopathy can continue even after the drug is stopped. “It’s thought to be a very mild but important risk,” said Nilanjana Bose, MD, MBA, a rheumatologist with Memorial Hermann Health System in Houston. “Patients taking HCQ must be screened for retinal issues, most certainly elderly patients and patients with any kind of comorbidities.”

“Examination alone is not sufficient to evaluate early changes, and specialized testing must be done. These include color photos, visual field tests, optical coherence tomography, fundus autofluorescence and in some cases, multifocal electroretinogram. Also, the AAO [American Academy of Ophthalmology] has specific recommendations related to Asian patients as they may have a different pattern of retinopathy that must also be considered.”
 

More accurate risk measurements

This news organization asked study coauthor April Jorge, MD, assistant professor of medicine in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, Boston, to discuss the study, how it correlates to past research, and what it adds that’s new and useful to rheumatologists and ophthalmologists:

Question: Your research found that a higher dose of HCQ in the first 5 years of treatment led to a greater risk of retinopathy. Is there any indication that a lower dose given more frequently, either within that 5-year period or longer, would pose a similar risk?

Answer: In our study, we assessed the HCQ dose in the first 5 years of use but followed patients who continued the medication longer than 5 years, through up to 15 years of use. Therefore, we compared the risk of HCQ retinopathy associated with different HCQ dosages but for the same duration of use. We found that for any dose of HCQ, the risk of retinopathy increases the longer the medication is used. However, patients who used a higher dose of HCQ had a higher risk of developing retinopathy over time.

Also unique to our study, we graded the severity of HCQ retinopathy outcomes. This was important, as we found that the majority of retinopathy cases detected through routine screening are mild and presumed to be asymptomatic. This will likely be reassuring news for patients that we can screen for this adverse event to detect it early and prevent vision loss.

Another important difference was that we assessed the risk of retinopathy associated with using over 6 mg/kg per day, between 5 and 6 mg/kg per day, and less than 5 mg/kg per day, whereas the highest dosing group assessed in the 2014 study included all patients using over 5 mg/kg per day. The risk was considerably higher in the > 6 mg/kg per day group than in the 5-6 mg/kg per day group.

Q: How can rheumatologists and ophthalmologists use this new information specifically to better treat their patients?

A: Our study provides more accurate estimates of the risk of HCQ retinopathy than in prior studies. These risk estimates can be used when rheumatologists (and other clinicians who prescribe HCQ) consider the risks and benefits of this otherwise important and well-tolerated medication. The risk associated with different dose ranges could also inform dosing decisions, since dosing over 6 mg/kg per day may be more of a concern than using doses in the 5-6 mg/kg range. Ophthalmologists can also use these new risk estimates to counsel patients of the importance of HCQ retinopathy screening and can also hopefully provide some reassurance to patients that the risk of severe retinopathy is low as long as they are being monitored.

The study authors were supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Rheumatology Research Foundation. The authors report no relevant financial relationships. Dr. Bose and Dr. Mirza had no relevant disclosures.

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

A new study likely makes the best estimate yet of the degree of retinopathy risk that patients who take the antimalarial drug hydroxychloroquine (HCQ) can expect, deriving mainly from the cumulative dose taken during the first 5 years of use, according to a study published in Annals of Internal Medicine.

HCQ works to decrease activity in a patient’s immune system, which is effective in many cases of systemic lupus erythematosus, one of the most common indications for the drug. However, an adverse outcome of treatment can be HCQ retinopathy, a progressive form of vision loss in patients taking HCQ over an extended period (mostly for longer than 5 years). The disease is often asymptomatic, although some patients do present a paracentral scotoma and a decrease in color vision. Patients may also notice flashing shapes in their vision and find that they have difficulty reading. Eventually, HCQ retinopathy can lead to loss of visual acuity, loss of peripheral vision, and loss of night vision.

Researchers from Kaiser Permanente Northern California and Harvard Medical School analyzed 3,325 persons who received HCQ for 5 or more years between 2004 and 2020. Their goal was to both characterize the long-term risk for incident HCQ retinopathy and examine the degree to which average HCQ dose within the first 5 years of treatment serves as a prediction of the risk.

The researchers then estimated the risk for developing retinopathy after 15 years, according to patients’ average dosing levels during the first 5 years of therapy. Overall, 81 participants developed HCQ retinopathy with overall cumulative incidences of 2.5% after 10 years and 8.6% after 15 years; the risk was greater for those given a higher dose during the first 5 years of treatment.

The mechanism of how HCQ toxicity may occur is still not completely known. There is evidence that toxicity happens because HCQ binds to melanin in both the retinal pigment epithelium and uvea in high concentrations. HCQ can interfere with lysosomal function, leading to oxidation and accumulation of lysosomes, which can cause dysfunction of the retinal pigment epithelium.

Progressive retinopathy can continue even after the drug is stopped. “It’s thought to be a very mild but important risk,” said Nilanjana Bose, MD, MBA, a rheumatologist with Memorial Hermann Health System in Houston. “Patients taking HCQ must be screened for retinal issues, most certainly elderly patients and patients with any kind of comorbidities.”

“Examination alone is not sufficient to evaluate early changes, and specialized testing must be done. These include color photos, visual field tests, optical coherence tomography, fundus autofluorescence and in some cases, multifocal electroretinogram. Also, the AAO [American Academy of Ophthalmology] has specific recommendations related to Asian patients as they may have a different pattern of retinopathy that must also be considered.”
 

More accurate risk measurements

This news organization asked study coauthor April Jorge, MD, assistant professor of medicine in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, Boston, to discuss the study, how it correlates to past research, and what it adds that’s new and useful to rheumatologists and ophthalmologists:

Question: Your research found that a higher dose of HCQ in the first 5 years of treatment led to a greater risk of retinopathy. Is there any indication that a lower dose given more frequently, either within that 5-year period or longer, would pose a similar risk?

Answer: In our study, we assessed the HCQ dose in the first 5 years of use but followed patients who continued the medication longer than 5 years, through up to 15 years of use. Therefore, we compared the risk of HCQ retinopathy associated with different HCQ dosages but for the same duration of use. We found that for any dose of HCQ, the risk of retinopathy increases the longer the medication is used. However, patients who used a higher dose of HCQ had a higher risk of developing retinopathy over time.

Also unique to our study, we graded the severity of HCQ retinopathy outcomes. This was important, as we found that the majority of retinopathy cases detected through routine screening are mild and presumed to be asymptomatic. This will likely be reassuring news for patients that we can screen for this adverse event to detect it early and prevent vision loss.

Another important difference was that we assessed the risk of retinopathy associated with using over 6 mg/kg per day, between 5 and 6 mg/kg per day, and less than 5 mg/kg per day, whereas the highest dosing group assessed in the 2014 study included all patients using over 5 mg/kg per day. The risk was considerably higher in the > 6 mg/kg per day group than in the 5-6 mg/kg per day group.

Q: How can rheumatologists and ophthalmologists use this new information specifically to better treat their patients?

A: Our study provides more accurate estimates of the risk of HCQ retinopathy than in prior studies. These risk estimates can be used when rheumatologists (and other clinicians who prescribe HCQ) consider the risks and benefits of this otherwise important and well-tolerated medication. The risk associated with different dose ranges could also inform dosing decisions, since dosing over 6 mg/kg per day may be more of a concern than using doses in the 5-6 mg/kg range. Ophthalmologists can also use these new risk estimates to counsel patients of the importance of HCQ retinopathy screening and can also hopefully provide some reassurance to patients that the risk of severe retinopathy is low as long as they are being monitored.

The study authors were supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Rheumatology Research Foundation. The authors report no relevant financial relationships. Dr. Bose and Dr. Mirza had no relevant disclosures.

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

A new study likely makes the best estimate yet of the degree of retinopathy risk that patients who take the antimalarial drug hydroxychloroquine (HCQ) can expect, deriving mainly from the cumulative dose taken during the first 5 years of use, according to a study published in Annals of Internal Medicine.

HCQ works to decrease activity in a patient’s immune system, which is effective in many cases of systemic lupus erythematosus, one of the most common indications for the drug. However, an adverse outcome of treatment can be HCQ retinopathy, a progressive form of vision loss in patients taking HCQ over an extended period (mostly for longer than 5 years). The disease is often asymptomatic, although some patients do present a paracentral scotoma and a decrease in color vision. Patients may also notice flashing shapes in their vision and find that they have difficulty reading. Eventually, HCQ retinopathy can lead to loss of visual acuity, loss of peripheral vision, and loss of night vision.

Researchers from Kaiser Permanente Northern California and Harvard Medical School analyzed 3,325 persons who received HCQ for 5 or more years between 2004 and 2020. Their goal was to both characterize the long-term risk for incident HCQ retinopathy and examine the degree to which average HCQ dose within the first 5 years of treatment serves as a prediction of the risk.

The researchers then estimated the risk for developing retinopathy after 15 years, according to patients’ average dosing levels during the first 5 years of therapy. Overall, 81 participants developed HCQ retinopathy with overall cumulative incidences of 2.5% after 10 years and 8.6% after 15 years; the risk was greater for those given a higher dose during the first 5 years of treatment.

The mechanism of how HCQ toxicity may occur is still not completely known. There is evidence that toxicity happens because HCQ binds to melanin in both the retinal pigment epithelium and uvea in high concentrations. HCQ can interfere with lysosomal function, leading to oxidation and accumulation of lysosomes, which can cause dysfunction of the retinal pigment epithelium.

Progressive retinopathy can continue even after the drug is stopped. “It’s thought to be a very mild but important risk,” said Nilanjana Bose, MD, MBA, a rheumatologist with Memorial Hermann Health System in Houston. “Patients taking HCQ must be screened for retinal issues, most certainly elderly patients and patients with any kind of comorbidities.”

“Examination alone is not sufficient to evaluate early changes, and specialized testing must be done. These include color photos, visual field tests, optical coherence tomography, fundus autofluorescence and in some cases, multifocal electroretinogram. Also, the AAO [American Academy of Ophthalmology] has specific recommendations related to Asian patients as they may have a different pattern of retinopathy that must also be considered.”
 

More accurate risk measurements

This news organization asked study coauthor April Jorge, MD, assistant professor of medicine in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, Boston, to discuss the study, how it correlates to past research, and what it adds that’s new and useful to rheumatologists and ophthalmologists:

Question: Your research found that a higher dose of HCQ in the first 5 years of treatment led to a greater risk of retinopathy. Is there any indication that a lower dose given more frequently, either within that 5-year period or longer, would pose a similar risk?

Answer: In our study, we assessed the HCQ dose in the first 5 years of use but followed patients who continued the medication longer than 5 years, through up to 15 years of use. Therefore, we compared the risk of HCQ retinopathy associated with different HCQ dosages but for the same duration of use. We found that for any dose of HCQ, the risk of retinopathy increases the longer the medication is used. However, patients who used a higher dose of HCQ had a higher risk of developing retinopathy over time.

Also unique to our study, we graded the severity of HCQ retinopathy outcomes. This was important, as we found that the majority of retinopathy cases detected through routine screening are mild and presumed to be asymptomatic. This will likely be reassuring news for patients that we can screen for this adverse event to detect it early and prevent vision loss.

Another important difference was that we assessed the risk of retinopathy associated with using over 6 mg/kg per day, between 5 and 6 mg/kg per day, and less than 5 mg/kg per day, whereas the highest dosing group assessed in the 2014 study included all patients using over 5 mg/kg per day. The risk was considerably higher in the > 6 mg/kg per day group than in the 5-6 mg/kg per day group.

Q: How can rheumatologists and ophthalmologists use this new information specifically to better treat their patients?

A: Our study provides more accurate estimates of the risk of HCQ retinopathy than in prior studies. These risk estimates can be used when rheumatologists (and other clinicians who prescribe HCQ) consider the risks and benefits of this otherwise important and well-tolerated medication. The risk associated with different dose ranges could also inform dosing decisions, since dosing over 6 mg/kg per day may be more of a concern than using doses in the 5-6 mg/kg range. Ophthalmologists can also use these new risk estimates to counsel patients of the importance of HCQ retinopathy screening and can also hopefully provide some reassurance to patients that the risk of severe retinopathy is low as long as they are being monitored.

The study authors were supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Rheumatology Research Foundation. The authors report no relevant financial relationships. Dr. Bose and Dr. Mirza had no relevant disclosures.

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

Hormone replacement therapy (HRT) introduced early during the menopausal transition may protect against Alzheimer’s dementia in women carrying the APOE4 gene, new research suggests.

Results from a cohort study of almost 1,200 women showed that use of HRT was associated with higher delayed memory scores and larger entorhinal and hippocampal brain volumes – areas that are affected early by Alzheimer’s disease (AD) pathology.

HRT was also found to be most effective, as seen by larger hippocampal volume, when introduced during early perimenopause.

“Clinicians are very much aware of the susceptibility of women to cognitive disturbances during menopause,” lead author Rasha Saleh, MD, senior research associate, University of East Anglia (England), said in an interview.

“Identifying the at-risk APOE4 women and early HRT introduction can be of benefit. Confirming our findings in a clinical trial would be the next step forward,” Dr. Saleh said.

The findings were published online in Alzheimer’s Research and Therapy.
 

Personalized approaches

Dr. Saleh noted that estrogen receptors are localized in various areas of the brain, including cognition-related areas. Estrogen regulates such things as neuroinflammatory status, glucose utilization, and lipid metabolism.

“The decline of estrogen during menopause can lead to disturbance in these functions, which can accelerate AD-related pathology,” she said.

HRT during the menopausal transition and afterward is “being considered as a strategy to mitigate cognitive decline,” the investigators wrote. Early observational studies have suggested that oral estrogen “may be protective against dementia,” but results of clinical trials have been inconsistent, and some have even shown “harmful effects.”

The current researchers were “interested in the personalized approaches in the prevention of AD,” Dr. Saleh said. Preclinical and pilot data from her group have shown that women with APOE4 have “better cognitive test scores with nutritional and hormonal interventions.”

This led Dr. Saleh to hypothesize that HRT would be of more cognitive benefit for those with versus without APOE4, particularly when introduced early during the menopausal transition.

To investigate this hypothesis, the researchers analyzed baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort. This project was initiated in 2015 with the aim of developing longitudinal models over the entire course of AD prior to dementia clinical diagnosis.

Participants were recruited from 10 European countries. All were required to be at least 50 years old, to have not been diagnosed with dementia at baseline, and to have no medical or psychiatric illness that could potentially exclude them from further research.

The current study included 1,178 women (mean age, 65.1 years), who were divided by genotype into non-APOE4 and APOE4 groups. HRT treatment for current or previous users included estrogen alone or estrogen plus progestogens via oral or transdermal administration routes, and at different doses.

The four tests used to assess cognition were the Mini-Mental State Examination dot counting to evaluate verbal working memory, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score, the Four Mountain Test, and the supermarket trolley virtual reality test.

Brain MRI data were collected. The researchers focused on the medial temporal lobe as the “main brain region regulating cognition and memory processing.” This lobe includes the hippocampus, the parahippocampus, the entorhinal cortex, and the amygdala.
 

‘Critical window’

The researchers found a “trend” toward an APOE-HRT interaction (P-interaction = .097) for the total RBANS score. In particular, it was significant for the RBANS delayed memory index, where scores were consistently higher for women with APOE4 who had received HRT, compared with all other groups (P-interaction = .009).

Within-genotype group comparisons showed that HRT users had a higher RBANS total scale score and delayed memory index (P = .045 and P = .002, respectively), but only among APOE4 carriers. Effect size analyses showed a large effect of HRT use on the Four Mountain Test score and the supermarket trolley virtual reality test score (Cohen’s d = 0.988 and 1.2, respectively).

“This large effect was found only in APOE4 carriers,” the investigators noted.

Similarly, a moderate to large effect of HRT on the left entorhinal volume was observed in APOE4 carriers (Cohen’s d = 0.63).

In members of the APOE4 group who received HRT, the left entorhinal and left and right amygdala volumes were larger, compared with both no-APOE4 and non-HRT users (P-interaction = .002, .003, and .005, respectively). Similar trends were observed for the right entorhinal volume (P = .074).

In addition, among HRT users, the left entorhinal volume was larger (P = .03); the right and left anterior cingulate gyrus volumes were smaller (P = .003 and .062, respectively); and the left superior frontal gyrus volume was larger (P = .009) in comparison with women who did not receive HRT, independently of their APOE genotype.

Early use of HRT among APOE4 carriers was associated with larger right and left hippocampal volume (P = .035 and P = .028, respectively) – an association not found in non-APOE4 carriers. The association was also not significant when participants were not stratified by APOE genotype.

“The key important point here is the timing, or the ‘critical window,’ when HRT can be of most benefit,” Dr. Saleh said. “This is most beneficial when introduced early, before the neuropathology becomes irreversible.”

Study limitations include its cross-sectional design, which precludes the establishment of a causal relationship, and the fact that information regarding the type and dose of estrogen was not available for all participants.

HRT is not without risk, Dr. Saleh noted. She recommended that clinicians “carry out various screening tests to make sure that a woman is eligible for HRT and not at risk of hypercoagulability, for instance.”
 

Risk-benefit ratio

In a comment, Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, called the study “exactly the kind of work that needs to be done.”

Dr. Fillit, who was not involved with the current research, is a clinical professor of geriatric medicine, palliative care medicine, and neuroscience at Mount Sinai Hospital, New York.

He compared the process with that of osteoporosis. “We know that if women are treated [with HRT] at the time of the menopause, you can prevent the rapid bone loss that occurs with rapid estrogen loss. But if you wait 5, 10 years out, once the bone loss has occurred, the HRT doesn’t really have any impact on osteoporosis risk because the horse is already out of the barn,” he said.

Although HRT carries risks, “they can clearly be managed; and if it’s proven that estrogen or hormone replacement around the time of the menopause can be protective [against AD], the risk-benefit ratio of HRT could be in favor of treatment,” Dr. Fillit added.

The study was conducted as part of the Medical Research Council NuBrain Consortium. The investigators and Dr. Fillit reported no relevant financial relationships.

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

Hormone replacement therapy (HRT) introduced early during the menopausal transition may protect against Alzheimer’s dementia in women carrying the APOE4 gene, new research suggests.

Results from a cohort study of almost 1,200 women showed that use of HRT was associated with higher delayed memory scores and larger entorhinal and hippocampal brain volumes – areas that are affected early by Alzheimer’s disease (AD) pathology.

HRT was also found to be most effective, as seen by larger hippocampal volume, when introduced during early perimenopause.

“Clinicians are very much aware of the susceptibility of women to cognitive disturbances during menopause,” lead author Rasha Saleh, MD, senior research associate, University of East Anglia (England), said in an interview.

“Identifying the at-risk APOE4 women and early HRT introduction can be of benefit. Confirming our findings in a clinical trial would be the next step forward,” Dr. Saleh said.

The findings were published online in Alzheimer’s Research and Therapy.
 

Personalized approaches

Dr. Saleh noted that estrogen receptors are localized in various areas of the brain, including cognition-related areas. Estrogen regulates such things as neuroinflammatory status, glucose utilization, and lipid metabolism.

“The decline of estrogen during menopause can lead to disturbance in these functions, which can accelerate AD-related pathology,” she said.

HRT during the menopausal transition and afterward is “being considered as a strategy to mitigate cognitive decline,” the investigators wrote. Early observational studies have suggested that oral estrogen “may be protective against dementia,” but results of clinical trials have been inconsistent, and some have even shown “harmful effects.”

The current researchers were “interested in the personalized approaches in the prevention of AD,” Dr. Saleh said. Preclinical and pilot data from her group have shown that women with APOE4 have “better cognitive test scores with nutritional and hormonal interventions.”

This led Dr. Saleh to hypothesize that HRT would be of more cognitive benefit for those with versus without APOE4, particularly when introduced early during the menopausal transition.

To investigate this hypothesis, the researchers analyzed baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort. This project was initiated in 2015 with the aim of developing longitudinal models over the entire course of AD prior to dementia clinical diagnosis.

Participants were recruited from 10 European countries. All were required to be at least 50 years old, to have not been diagnosed with dementia at baseline, and to have no medical or psychiatric illness that could potentially exclude them from further research.

The current study included 1,178 women (mean age, 65.1 years), who were divided by genotype into non-APOE4 and APOE4 groups. HRT treatment for current or previous users included estrogen alone or estrogen plus progestogens via oral or transdermal administration routes, and at different doses.

The four tests used to assess cognition were the Mini-Mental State Examination dot counting to evaluate verbal working memory, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score, the Four Mountain Test, and the supermarket trolley virtual reality test.

Brain MRI data were collected. The researchers focused on the medial temporal lobe as the “main brain region regulating cognition and memory processing.” This lobe includes the hippocampus, the parahippocampus, the entorhinal cortex, and the amygdala.
 

‘Critical window’

The researchers found a “trend” toward an APOE-HRT interaction (P-interaction = .097) for the total RBANS score. In particular, it was significant for the RBANS delayed memory index, where scores were consistently higher for women with APOE4 who had received HRT, compared with all other groups (P-interaction = .009).

Within-genotype group comparisons showed that HRT users had a higher RBANS total scale score and delayed memory index (P = .045 and P = .002, respectively), but only among APOE4 carriers. Effect size analyses showed a large effect of HRT use on the Four Mountain Test score and the supermarket trolley virtual reality test score (Cohen’s d = 0.988 and 1.2, respectively).

“This large effect was found only in APOE4 carriers,” the investigators noted.

Similarly, a moderate to large effect of HRT on the left entorhinal volume was observed in APOE4 carriers (Cohen’s d = 0.63).

In members of the APOE4 group who received HRT, the left entorhinal and left and right amygdala volumes were larger, compared with both no-APOE4 and non-HRT users (P-interaction = .002, .003, and .005, respectively). Similar trends were observed for the right entorhinal volume (P = .074).

In addition, among HRT users, the left entorhinal volume was larger (P = .03); the right and left anterior cingulate gyrus volumes were smaller (P = .003 and .062, respectively); and the left superior frontal gyrus volume was larger (P = .009) in comparison with women who did not receive HRT, independently of their APOE genotype.

Early use of HRT among APOE4 carriers was associated with larger right and left hippocampal volume (P = .035 and P = .028, respectively) – an association not found in non-APOE4 carriers. The association was also not significant when participants were not stratified by APOE genotype.

“The key important point here is the timing, or the ‘critical window,’ when HRT can be of most benefit,” Dr. Saleh said. “This is most beneficial when introduced early, before the neuropathology becomes irreversible.”

Study limitations include its cross-sectional design, which precludes the establishment of a causal relationship, and the fact that information regarding the type and dose of estrogen was not available for all participants.

HRT is not without risk, Dr. Saleh noted. She recommended that clinicians “carry out various screening tests to make sure that a woman is eligible for HRT and not at risk of hypercoagulability, for instance.”
 

Risk-benefit ratio

In a comment, Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, called the study “exactly the kind of work that needs to be done.”

Dr. Fillit, who was not involved with the current research, is a clinical professor of geriatric medicine, palliative care medicine, and neuroscience at Mount Sinai Hospital, New York.

He compared the process with that of osteoporosis. “We know that if women are treated [with HRT] at the time of the menopause, you can prevent the rapid bone loss that occurs with rapid estrogen loss. But if you wait 5, 10 years out, once the bone loss has occurred, the HRT doesn’t really have any impact on osteoporosis risk because the horse is already out of the barn,” he said.

Although HRT carries risks, “they can clearly be managed; and if it’s proven that estrogen or hormone replacement around the time of the menopause can be protective [against AD], the risk-benefit ratio of HRT could be in favor of treatment,” Dr. Fillit added.

The study was conducted as part of the Medical Research Council NuBrain Consortium. The investigators and Dr. Fillit reported no relevant financial relationships.

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

Hormone replacement therapy (HRT) introduced early during the menopausal transition may protect against Alzheimer’s dementia in women carrying the APOE4 gene, new research suggests.

Results from a cohort study of almost 1,200 women showed that use of HRT was associated with higher delayed memory scores and larger entorhinal and hippocampal brain volumes – areas that are affected early by Alzheimer’s disease (AD) pathology.

HRT was also found to be most effective, as seen by larger hippocampal volume, when introduced during early perimenopause.

“Clinicians are very much aware of the susceptibility of women to cognitive disturbances during menopause,” lead author Rasha Saleh, MD, senior research associate, University of East Anglia (England), said in an interview.

“Identifying the at-risk APOE4 women and early HRT introduction can be of benefit. Confirming our findings in a clinical trial would be the next step forward,” Dr. Saleh said.

The findings were published online in Alzheimer’s Research and Therapy.
 

Personalized approaches

Dr. Saleh noted that estrogen receptors are localized in various areas of the brain, including cognition-related areas. Estrogen regulates such things as neuroinflammatory status, glucose utilization, and lipid metabolism.

“The decline of estrogen during menopause can lead to disturbance in these functions, which can accelerate AD-related pathology,” she said.

HRT during the menopausal transition and afterward is “being considered as a strategy to mitigate cognitive decline,” the investigators wrote. Early observational studies have suggested that oral estrogen “may be protective against dementia,” but results of clinical trials have been inconsistent, and some have even shown “harmful effects.”

The current researchers were “interested in the personalized approaches in the prevention of AD,” Dr. Saleh said. Preclinical and pilot data from her group have shown that women with APOE4 have “better cognitive test scores with nutritional and hormonal interventions.”

This led Dr. Saleh to hypothesize that HRT would be of more cognitive benefit for those with versus without APOE4, particularly when introduced early during the menopausal transition.

To investigate this hypothesis, the researchers analyzed baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort. This project was initiated in 2015 with the aim of developing longitudinal models over the entire course of AD prior to dementia clinical diagnosis.

Participants were recruited from 10 European countries. All were required to be at least 50 years old, to have not been diagnosed with dementia at baseline, and to have no medical or psychiatric illness that could potentially exclude them from further research.

The current study included 1,178 women (mean age, 65.1 years), who were divided by genotype into non-APOE4 and APOE4 groups. HRT treatment for current or previous users included estrogen alone or estrogen plus progestogens via oral or transdermal administration routes, and at different doses.

The four tests used to assess cognition were the Mini-Mental State Examination dot counting to evaluate verbal working memory, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score, the Four Mountain Test, and the supermarket trolley virtual reality test.

Brain MRI data were collected. The researchers focused on the medial temporal lobe as the “main brain region regulating cognition and memory processing.” This lobe includes the hippocampus, the parahippocampus, the entorhinal cortex, and the amygdala.
 

‘Critical window’

The researchers found a “trend” toward an APOE-HRT interaction (P-interaction = .097) for the total RBANS score. In particular, it was significant for the RBANS delayed memory index, where scores were consistently higher for women with APOE4 who had received HRT, compared with all other groups (P-interaction = .009).

Within-genotype group comparisons showed that HRT users had a higher RBANS total scale score and delayed memory index (P = .045 and P = .002, respectively), but only among APOE4 carriers. Effect size analyses showed a large effect of HRT use on the Four Mountain Test score and the supermarket trolley virtual reality test score (Cohen’s d = 0.988 and 1.2, respectively).

“This large effect was found only in APOE4 carriers,” the investigators noted.

Similarly, a moderate to large effect of HRT on the left entorhinal volume was observed in APOE4 carriers (Cohen’s d = 0.63).

In members of the APOE4 group who received HRT, the left entorhinal and left and right amygdala volumes were larger, compared with both no-APOE4 and non-HRT users (P-interaction = .002, .003, and .005, respectively). Similar trends were observed for the right entorhinal volume (P = .074).

In addition, among HRT users, the left entorhinal volume was larger (P = .03); the right and left anterior cingulate gyrus volumes were smaller (P = .003 and .062, respectively); and the left superior frontal gyrus volume was larger (P = .009) in comparison with women who did not receive HRT, independently of their APOE genotype.

Early use of HRT among APOE4 carriers was associated with larger right and left hippocampal volume (P = .035 and P = .028, respectively) – an association not found in non-APOE4 carriers. The association was also not significant when participants were not stratified by APOE genotype.

“The key important point here is the timing, or the ‘critical window,’ when HRT can be of most benefit,” Dr. Saleh said. “This is most beneficial when introduced early, before the neuropathology becomes irreversible.”

Study limitations include its cross-sectional design, which precludes the establishment of a causal relationship, and the fact that information regarding the type and dose of estrogen was not available for all participants.

HRT is not without risk, Dr. Saleh noted. She recommended that clinicians “carry out various screening tests to make sure that a woman is eligible for HRT and not at risk of hypercoagulability, for instance.”
 

Risk-benefit ratio

In a comment, Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, called the study “exactly the kind of work that needs to be done.”

Dr. Fillit, who was not involved with the current research, is a clinical professor of geriatric medicine, palliative care medicine, and neuroscience at Mount Sinai Hospital, New York.

He compared the process with that of osteoporosis. “We know that if women are treated [with HRT] at the time of the menopause, you can prevent the rapid bone loss that occurs with rapid estrogen loss. But if you wait 5, 10 years out, once the bone loss has occurred, the HRT doesn’t really have any impact on osteoporosis risk because the horse is already out of the barn,” he said.

Although HRT carries risks, “they can clearly be managed; and if it’s proven that estrogen or hormone replacement around the time of the menopause can be protective [against AD], the risk-benefit ratio of HRT could be in favor of treatment,” Dr. Fillit added.

The study was conducted as part of the Medical Research Council NuBrain Consortium. The investigators and Dr. Fillit reported no relevant financial relationships.

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

Tissue plasminogen activator (t-PA) has been the standard IV thrombolytic used in acute ischemic stroke treatment since its US Food and Drug Administration (FDA) approval in 1995. Trials have established this drug’s efficacy in the treatment of acute ischemic stroke and the appropriate patient population for therapy.^1-3 Published guidelines and experiences have made clear that a written protocol with extensive personnel training is important to deliver this care properly.⁴

Tenecteplase has been available for use in the treatment of acute myocardial infarction (MI) and studied in acute ischemic strokes since 2000. Recent large multicenter trials have suggested tenecteplase may work better than t-PA in the recanalization of large vessel occlusions (LVOs) and have provided guidance on proper dosing in acute ischemic stroke victims.^5-8 Compared with t-PA, tenecteplase has a longer half-life, is more fibrin specific (causing less coagulopathy), and is more resistant to endogenous plasminogen activator inhibitor.^9,10 Using tenecteplase for acute ischemic stroke is simpler as a single dose bolus rather than a bolus followed by a 1-hour infusion with t-PA. Immediate mechanical thrombectomy for LVO is less complicated without the 1-hour t-PA infusion.^5,6 Tenecteplase use also allows for nonthrombectomy hospitals to accelerate transfer times for patients who need thrombectomy following thrombolysis by eliminating the need for critical care nurse–staffed ambulances for interfacility transfer.¹¹ Tenecteplase also is cheaper: Tenecteplase costs $3748 per vial, whereas t-PA costs $5800 per vial equating to roughly a $2000 savings per patient.^12,13 Finally, the pharmacy formulary is simplified by using a single thrombolytic agent for both cardiac and neurologic emergencies.

Tenecteplase does have some drawbacks to consider. Currently, tenecteplase is not approved by the FDA for the indication of acute ischemic stroke, though the drug is endorsed by the American Heart Association stroke guidelines of 2019 as an alternative to t-PA.¹⁴ There is no stroke-specific preparation of the drug, leading to potential dosing errors. Therefore, a systematic process to safely transition from t-PA to tenecteplase for acute ischemic stroke was undertaken at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. Here, we report the process required in making a complex switch in thrombolytic medication along with the potential benefits of making this transition.

OBSERVATIONS

The process to implement tenecteplase required extensive training and education for staff physicians, nurses, pharmacists, radiologists, trainees, and the rapid response team. Our institution administered IV thrombolytic drugs up to 25 times annually to acute ischemic stroke victims, meaning we had to train personnel extensively and repeatedly.

In preparation for the transition to tenecteplase, hospital leadership gathered staff for multidisciplinary administrative meetings that included neurology, emergency medicine, intensive care, pharmacy, radiology, and nursing departments. The purpose of these meetings was to establish a standard operating procedure (SOP) to ensure a safe transition. This process began in May 2020 and involved regular meetings to draft and revise our SOP. Additionally, several leadership and training sessions were held over a 6-month period. Stroke boxes were developed that contained the required evaluation tools, consent forms, medications (tenecteplase and treatments for known complications), dosing cards, and instructions. Final approval of the updated acute ischemic stroke hospital policy was obtained in November 2020 and signed by the above departments.

All inclusion and exclusion criteria were determined to be the same for tenecteplase as they were for t-PA with the notable exception that the WAKE-UP trial protocol would not be supported until further evidence became available.⁹ The results of the WAKE-UP trial had previously been used at WRNMMC to justify administration of t-PA in patients who awoke with symptoms of acute ischemic stroke, the last known well was unclear or > 4.5 hours, and for whom a magnetic resonance imaging (MRI) of the brain could be obtained rapidly. Based on the WAKE-UP trial, if the MRI scan of the brain in these patients demonstrated restricted diffusion without fluid attenuated inversion recovery (FLAIR) signal changes (diffusion-weighted [DWI]-FLAIR mismatch sign), this indicated that the stroke had likely occurred recently, and it was safe to administer t-PA. This allowed for administration of t-PA outside the standard treatment window of 4.5 hours from last known well, especially in the cases of patients who awoke with symptoms.

Since safety data are not yet available for the use of tenecteplase in this fashion, the WAKE-UP trial protocol was not used as an inclusion criterion. The informed consent form was modified, and the following scenarios were outlined: (1) If the patient or surrogate is immediately available to consent, paper consent will be documented with the additional note that tenecteplase is being used off-label; and (2) If the patient cannot consent and a surrogate is not immediately available, the medicine will be used emergently as long as the neurology resident and attending physicians agree.¹⁵

Risk mitigation was considered carefully. The stroke box described above is stocked and maintained by the pharmacy as we have transitioned to using designated pharmacists for the storage and preparation of tenecteplase. We highly recommend the use of designated pharmacists or emergency department pharmacists in this manner to avoid dosing errors.^7,16 Since the current pharmacy-provided tenecteplase bottle contains twice the maximum dose indicated for ischemic stroke, only a 5 mL syringe is included in the stroke box to ensure a maximum dose of 25 mg is drawn up after reconstitution. Dosing card charts were made like existing dosing card charts for t-PA to quickly calculate the 0.25 mg/kg dose. In training, the difference in dosing in ischemic stroke was emphasized. Finally, pharmacy has taken responsibility for dosing the medication during stroke codes.

Any medical personnel at WRNMMC can initiate a stroke code by sending a page to the neurology consult service (Figure).

TRANSITION AND RESULTS

From November 2020 to December 2021, 10 patients have been treated in total at WRNMMC (Table).

CONCLUSIONS

The available evidence supports the transition from t-PA to tenecteplase for acute ischemic stroke. The successful transition required months of preparation involving multidisciplinary meetings between neurology, nursing, pharmacy, radiology, rapid response teams, critical care, and emergency medicine departments. Safeguards must be implemented to avoid a tenecteplase dosing error that can lead to potentially life-threatening adverse effects. The results at WRNMMC thus far are promising for safety and efficacy. Several process improvements are planned: a hospital-wide overhead page will accompany the direct page to neurology; other team members, including radiology and pharmacy, will be included on the acute stroke alert; and a stroke-specific paging application will be implemented to better track real-time stroke metrics and improve flow. These measures mirror processes that are occurring in institutions that treat acute stroke patients.

Tissue plasminogen activator (t-PA) has been the standard IV thrombolytic used in acute ischemic stroke treatment since its US Food and Drug Administration (FDA) approval in 1995. Trials have established this drug’s efficacy in the treatment of acute ischemic stroke and the appropriate patient population for therapy.^1-3 Published guidelines and experiences have made clear that a written protocol with extensive personnel training is important to deliver this care properly.⁴

Tenecteplase has been available for use in the treatment of acute myocardial infarction (MI) and studied in acute ischemic strokes since 2000. Recent large multicenter trials have suggested tenecteplase may work better than t-PA in the recanalization of large vessel occlusions (LVOs) and have provided guidance on proper dosing in acute ischemic stroke victims.^5-8 Compared with t-PA, tenecteplase has a longer half-life, is more fibrin specific (causing less coagulopathy), and is more resistant to endogenous plasminogen activator inhibitor.^9,10 Using tenecteplase for acute ischemic stroke is simpler as a single dose bolus rather than a bolus followed by a 1-hour infusion with t-PA. Immediate mechanical thrombectomy for LVO is less complicated without the 1-hour t-PA infusion.^5,6 Tenecteplase use also allows for nonthrombectomy hospitals to accelerate transfer times for patients who need thrombectomy following thrombolysis by eliminating the need for critical care nurse–staffed ambulances for interfacility transfer.¹¹ Tenecteplase also is cheaper: Tenecteplase costs $3748 per vial, whereas t-PA costs $5800 per vial equating to roughly a $2000 savings per patient.^12,13 Finally, the pharmacy formulary is simplified by using a single thrombolytic agent for both cardiac and neurologic emergencies.

Tenecteplase does have some drawbacks to consider. Currently, tenecteplase is not approved by the FDA for the indication of acute ischemic stroke, though the drug is endorsed by the American Heart Association stroke guidelines of 2019 as an alternative to t-PA.¹⁴ There is no stroke-specific preparation of the drug, leading to potential dosing errors. Therefore, a systematic process to safely transition from t-PA to tenecteplase for acute ischemic stroke was undertaken at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. Here, we report the process required in making a complex switch in thrombolytic medication along with the potential benefits of making this transition.

OBSERVATIONS

The process to implement tenecteplase required extensive training and education for staff physicians, nurses, pharmacists, radiologists, trainees, and the rapid response team. Our institution administered IV thrombolytic drugs up to 25 times annually to acute ischemic stroke victims, meaning we had to train personnel extensively and repeatedly.

In preparation for the transition to tenecteplase, hospital leadership gathered staff for multidisciplinary administrative meetings that included neurology, emergency medicine, intensive care, pharmacy, radiology, and nursing departments. The purpose of these meetings was to establish a standard operating procedure (SOP) to ensure a safe transition. This process began in May 2020 and involved regular meetings to draft and revise our SOP. Additionally, several leadership and training sessions were held over a 6-month period. Stroke boxes were developed that contained the required evaluation tools, consent forms, medications (tenecteplase and treatments for known complications), dosing cards, and instructions. Final approval of the updated acute ischemic stroke hospital policy was obtained in November 2020 and signed by the above departments.

All inclusion and exclusion criteria were determined to be the same for tenecteplase as they were for t-PA with the notable exception that the WAKE-UP trial protocol would not be supported until further evidence became available.⁹ The results of the WAKE-UP trial had previously been used at WRNMMC to justify administration of t-PA in patients who awoke with symptoms of acute ischemic stroke, the last known well was unclear or > 4.5 hours, and for whom a magnetic resonance imaging (MRI) of the brain could be obtained rapidly. Based on the WAKE-UP trial, if the MRI scan of the brain in these patients demonstrated restricted diffusion without fluid attenuated inversion recovery (FLAIR) signal changes (diffusion-weighted [DWI]-FLAIR mismatch sign), this indicated that the stroke had likely occurred recently, and it was safe to administer t-PA. This allowed for administration of t-PA outside the standard treatment window of 4.5 hours from last known well, especially in the cases of patients who awoke with symptoms.

Since safety data are not yet available for the use of tenecteplase in this fashion, the WAKE-UP trial protocol was not used as an inclusion criterion. The informed consent form was modified, and the following scenarios were outlined: (1) If the patient or surrogate is immediately available to consent, paper consent will be documented with the additional note that tenecteplase is being used off-label; and (2) If the patient cannot consent and a surrogate is not immediately available, the medicine will be used emergently as long as the neurology resident and attending physicians agree.¹⁵

Risk mitigation was considered carefully. The stroke box described above is stocked and maintained by the pharmacy as we have transitioned to using designated pharmacists for the storage and preparation of tenecteplase. We highly recommend the use of designated pharmacists or emergency department pharmacists in this manner to avoid dosing errors.^7,16 Since the current pharmacy-provided tenecteplase bottle contains twice the maximum dose indicated for ischemic stroke, only a 5 mL syringe is included in the stroke box to ensure a maximum dose of 25 mg is drawn up after reconstitution. Dosing card charts were made like existing dosing card charts for t-PA to quickly calculate the 0.25 mg/kg dose. In training, the difference in dosing in ischemic stroke was emphasized. Finally, pharmacy has taken responsibility for dosing the medication during stroke codes.

Any medical personnel at WRNMMC can initiate a stroke code by sending a page to the neurology consult service (Figure).

TRANSITION AND RESULTS

From November 2020 to December 2021, 10 patients have been treated in total at WRNMMC (Table).

CONCLUSIONS

The available evidence supports the transition from t-PA to tenecteplase for acute ischemic stroke. The successful transition required months of preparation involving multidisciplinary meetings between neurology, nursing, pharmacy, radiology, rapid response teams, critical care, and emergency medicine departments. Safeguards must be implemented to avoid a tenecteplase dosing error that can lead to potentially life-threatening adverse effects. The results at WRNMMC thus far are promising for safety and efficacy. Several process improvements are planned: a hospital-wide overhead page will accompany the direct page to neurology; other team members, including radiology and pharmacy, will be included on the acute stroke alert; and a stroke-specific paging application will be implemented to better track real-time stroke metrics and improve flow. These measures mirror processes that are occurring in institutions that treat acute stroke patients.

Tissue plasminogen activator (t-PA) has been the standard IV thrombolytic used in acute ischemic stroke treatment since its US Food and Drug Administration (FDA) approval in 1995. Trials have established this drug’s efficacy in the treatment of acute ischemic stroke and the appropriate patient population for therapy.^1-3 Published guidelines and experiences have made clear that a written protocol with extensive personnel training is important to deliver this care properly.⁴

Tenecteplase has been available for use in the treatment of acute myocardial infarction (MI) and studied in acute ischemic strokes since 2000. Recent large multicenter trials have suggested tenecteplase may work better than t-PA in the recanalization of large vessel occlusions (LVOs) and have provided guidance on proper dosing in acute ischemic stroke victims.^5-8 Compared with t-PA, tenecteplase has a longer half-life, is more fibrin specific (causing less coagulopathy), and is more resistant to endogenous plasminogen activator inhibitor.^9,10 Using tenecteplase for acute ischemic stroke is simpler as a single dose bolus rather than a bolus followed by a 1-hour infusion with t-PA. Immediate mechanical thrombectomy for LVO is less complicated without the 1-hour t-PA infusion.^5,6 Tenecteplase use also allows for nonthrombectomy hospitals to accelerate transfer times for patients who need thrombectomy following thrombolysis by eliminating the need for critical care nurse–staffed ambulances for interfacility transfer.¹¹ Tenecteplase also is cheaper: Tenecteplase costs $3748 per vial, whereas t-PA costs $5800 per vial equating to roughly a $2000 savings per patient.^12,13 Finally, the pharmacy formulary is simplified by using a single thrombolytic agent for both cardiac and neurologic emergencies.

Tenecteplase does have some drawbacks to consider. Currently, tenecteplase is not approved by the FDA for the indication of acute ischemic stroke, though the drug is endorsed by the American Heart Association stroke guidelines of 2019 as an alternative to t-PA.¹⁴ There is no stroke-specific preparation of the drug, leading to potential dosing errors. Therefore, a systematic process to safely transition from t-PA to tenecteplase for acute ischemic stroke was undertaken at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. Here, we report the process required in making a complex switch in thrombolytic medication along with the potential benefits of making this transition.

OBSERVATIONS

The process to implement tenecteplase required extensive training and education for staff physicians, nurses, pharmacists, radiologists, trainees, and the rapid response team. Our institution administered IV thrombolytic drugs up to 25 times annually to acute ischemic stroke victims, meaning we had to train personnel extensively and repeatedly.

In preparation for the transition to tenecteplase, hospital leadership gathered staff for multidisciplinary administrative meetings that included neurology, emergency medicine, intensive care, pharmacy, radiology, and nursing departments. The purpose of these meetings was to establish a standard operating procedure (SOP) to ensure a safe transition. This process began in May 2020 and involved regular meetings to draft and revise our SOP. Additionally, several leadership and training sessions were held over a 6-month period. Stroke boxes were developed that contained the required evaluation tools, consent forms, medications (tenecteplase and treatments for known complications), dosing cards, and instructions. Final approval of the updated acute ischemic stroke hospital policy was obtained in November 2020 and signed by the above departments.

All inclusion and exclusion criteria were determined to be the same for tenecteplase as they were for t-PA with the notable exception that the WAKE-UP trial protocol would not be supported until further evidence became available.⁹ The results of the WAKE-UP trial had previously been used at WRNMMC to justify administration of t-PA in patients who awoke with symptoms of acute ischemic stroke, the last known well was unclear or > 4.5 hours, and for whom a magnetic resonance imaging (MRI) of the brain could be obtained rapidly. Based on the WAKE-UP trial, if the MRI scan of the brain in these patients demonstrated restricted diffusion without fluid attenuated inversion recovery (FLAIR) signal changes (diffusion-weighted [DWI]-FLAIR mismatch sign), this indicated that the stroke had likely occurred recently, and it was safe to administer t-PA. This allowed for administration of t-PA outside the standard treatment window of 4.5 hours from last known well, especially in the cases of patients who awoke with symptoms.

Since safety data are not yet available for the use of tenecteplase in this fashion, the WAKE-UP trial protocol was not used as an inclusion criterion. The informed consent form was modified, and the following scenarios were outlined: (1) If the patient or surrogate is immediately available to consent, paper consent will be documented with the additional note that tenecteplase is being used off-label; and (2) If the patient cannot consent and a surrogate is not immediately available, the medicine will be used emergently as long as the neurology resident and attending physicians agree.¹⁵

Risk mitigation was considered carefully. The stroke box described above is stocked and maintained by the pharmacy as we have transitioned to using designated pharmacists for the storage and preparation of tenecteplase. We highly recommend the use of designated pharmacists or emergency department pharmacists in this manner to avoid dosing errors.^7,16 Since the current pharmacy-provided tenecteplase bottle contains twice the maximum dose indicated for ischemic stroke, only a 5 mL syringe is included in the stroke box to ensure a maximum dose of 25 mg is drawn up after reconstitution. Dosing card charts were made like existing dosing card charts for t-PA to quickly calculate the 0.25 mg/kg dose. In training, the difference in dosing in ischemic stroke was emphasized. Finally, pharmacy has taken responsibility for dosing the medication during stroke codes.

Any medical personnel at WRNMMC can initiate a stroke code by sending a page to the neurology consult service (Figure).

TRANSITION AND RESULTS

From November 2020 to December 2021, 10 patients have been treated in total at WRNMMC (Table).

CONCLUSIONS

The available evidence supports the transition from t-PA to tenecteplase for acute ischemic stroke. The successful transition required months of preparation involving multidisciplinary meetings between neurology, nursing, pharmacy, radiology, rapid response teams, critical care, and emergency medicine departments. Safeguards must be implemented to avoid a tenecteplase dosing error that can lead to potentially life-threatening adverse effects. The results at WRNMMC thus far are promising for safety and efficacy. Several process improvements are planned: a hospital-wide overhead page will accompany the direct page to neurology; other team members, including radiology and pharmacy, will be included on the acute stroke alert; and a stroke-specific paging application will be implemented to better track real-time stroke metrics and improve flow. These measures mirror processes that are occurring in institutions that treat acute stroke patients.

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

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

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

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

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

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