Literature Review

A blood test that measures elevations in neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS) could warn of worsening disability up to 2 years before it occurs, a new study suggests.

Rising NfL levels are a known indicator of neuroaxonal injury and correlate with MS disease activity. Levels rise in the presence of an MS relapse or MRI activity and fall following treatment with disease-modifying therapies. But the link between NfL levels and worsening disability was less understood.

This new analysis of NfL in two large MS cohorts found that elevated levels of the neuronal protein at baseline were associated with large increases in future disability risk, even in patients with no clinical relapse.

“This rising of NfL up to 2 years before signs of disability worsening represents the window when interventions may prevent worsening,” lead investigator Ahmed Abdelhak, MD, department of neurology, University of California, San Francisco, said in a press release.

The findings were published online in JAMA Neurology.
 

Early warning system?

The study included data on 1,899 patients with nearly 13,000 patient visits from two observational, long-term, real-world cohorts: the U.S.-based Expression, Proteomics, Imaging, Clinical (EPIC) study (n = 609 patients), and the Swiss Multiple Sclerosis Cohort trial (SMSC; n = 1,290 patients).

Investigators analyzed longitudinal serum NfL measurements in conjunction with clinical disability worsening, defined as 6 months or more of increased impairment as measured by the Expanded Disability Status Scale.

Researchers also assessed the temporal association between NfL measurements and the risk of increased disability and distinguished between disability with and without relapse.

Worsening disability was reported in 227 patients in the EPIC group and 435 in the SMSC trial.

Elevated NfL at baseline was associated with a 70% higher risk for worsening disability with relapse about 11 months later in the SMSC study (hazard ratio, 1.70; P = .02). In the EPIC trial, there was trend toward a 91% higher risk for worsening disability with relapse at 12.6 months, although the findings did not meet statistical significance (HR, 1.91; P = .07).

The risk of future disability progression independent of clinical relapse was 40% higher in those with high NfL at baseline in the EPIC study 12 months after baseline (HR, 1.40; P = .02) and 49% higher in the SMSC trial 21 months later (HR, 1.49; P < .001).

The early elevation of NfL levels suggests a slower degradation of nerve cells and could be a possible early warning system of future progression of disability, allowing time for interventions that could slow or even halt further disability.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” senior author Jens Kuhle, MD, PhD, leader of the Swiss cohort and head of the Multiple Sclerosis Center at University Hospital and University of Basel, said in a statement.
 

Challenges for clinicians

Commenting on the findings, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research, Neurological Institute, Cleveland Clinic, said that, while there is a clinical test to measure NfL levels, incorporating that test into standard of care isn’t straightforward.

“The challenge for the practicing clinician is to translate these population-level studies to individual patient management decisions,” said Dr. Fox, who was not a part of the study.

“The published prediction curves corrected for age, sex, disease course, disease-modifying treatment, relapse within the past 90 days, and current disability status, the combination of which makes it rather challenging to calculate and interpret adjusted z score NfL levels in routine practice and then use it in clinical decision-making.”

The investigators said the study underscores the importance of NfL as an MS biomarker and “points to the existence of different windows of dynamic central nervous system pathology” that precedes worsening disability with or without relapse. But there may be a simpler explanation, Dr. Fox suggested.

“We know MRI activity occurs 5-10 times more frequently than relapses, and we know that MRI activity is associated with both NfL increases and future disability progression,” Dr. Fox said. “It is quite likely that the elevations in NfL seen here are reflective of new MRI disease activity, which frequently is seen without symptoms of an MS relapse,” he said

The study was funded by the Westridge Foundation, F. Hoffmann–La Roche, the Fishman Family, the Swiss National Research Foundation, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the Valhalla Foundation. Dr. Abdelhak reported receiving grants from the German Multiple Sclerosis Society and the Weill Institute for Neurosciences outside the submitted work. Dr. Kuhle has received grants from Swiss MS Society, the Swiss National Research Foundation, the Progressive MS Alliance, Biogen, Merck, Celgene, Bristol-Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and the University of Basel outside the submitted work. Dr. Fox reported receiving consulting fees from Siemens and Roche.

A version of this article appeared on Medscape.com.

A blood test that measures elevations in neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS) could warn of worsening disability up to 2 years before it occurs, a new study suggests.

Rising NfL levels are a known indicator of neuroaxonal injury and correlate with MS disease activity. Levels rise in the presence of an MS relapse or MRI activity and fall following treatment with disease-modifying therapies. But the link between NfL levels and worsening disability was less understood.

This new analysis of NfL in two large MS cohorts found that elevated levels of the neuronal protein at baseline were associated with large increases in future disability risk, even in patients with no clinical relapse.

“This rising of NfL up to 2 years before signs of disability worsening represents the window when interventions may prevent worsening,” lead investigator Ahmed Abdelhak, MD, department of neurology, University of California, San Francisco, said in a press release.

The findings were published online in JAMA Neurology.
 

Early warning system?

The study included data on 1,899 patients with nearly 13,000 patient visits from two observational, long-term, real-world cohorts: the U.S.-based Expression, Proteomics, Imaging, Clinical (EPIC) study (n = 609 patients), and the Swiss Multiple Sclerosis Cohort trial (SMSC; n = 1,290 patients).

Investigators analyzed longitudinal serum NfL measurements in conjunction with clinical disability worsening, defined as 6 months or more of increased impairment as measured by the Expanded Disability Status Scale.

Researchers also assessed the temporal association between NfL measurements and the risk of increased disability and distinguished between disability with and without relapse.

Worsening disability was reported in 227 patients in the EPIC group and 435 in the SMSC trial.

Elevated NfL at baseline was associated with a 70% higher risk for worsening disability with relapse about 11 months later in the SMSC study (hazard ratio, 1.70; P = .02). In the EPIC trial, there was trend toward a 91% higher risk for worsening disability with relapse at 12.6 months, although the findings did not meet statistical significance (HR, 1.91; P = .07).

The risk of future disability progression independent of clinical relapse was 40% higher in those with high NfL at baseline in the EPIC study 12 months after baseline (HR, 1.40; P = .02) and 49% higher in the SMSC trial 21 months later (HR, 1.49; P < .001).

The early elevation of NfL levels suggests a slower degradation of nerve cells and could be a possible early warning system of future progression of disability, allowing time for interventions that could slow or even halt further disability.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” senior author Jens Kuhle, MD, PhD, leader of the Swiss cohort and head of the Multiple Sclerosis Center at University Hospital and University of Basel, said in a statement.
 

Challenges for clinicians

Commenting on the findings, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research, Neurological Institute, Cleveland Clinic, said that, while there is a clinical test to measure NfL levels, incorporating that test into standard of care isn’t straightforward.

“The challenge for the practicing clinician is to translate these population-level studies to individual patient management decisions,” said Dr. Fox, who was not a part of the study.

“The published prediction curves corrected for age, sex, disease course, disease-modifying treatment, relapse within the past 90 days, and current disability status, the combination of which makes it rather challenging to calculate and interpret adjusted z score NfL levels in routine practice and then use it in clinical decision-making.”

The investigators said the study underscores the importance of NfL as an MS biomarker and “points to the existence of different windows of dynamic central nervous system pathology” that precedes worsening disability with or without relapse. But there may be a simpler explanation, Dr. Fox suggested.

“We know MRI activity occurs 5-10 times more frequently than relapses, and we know that MRI activity is associated with both NfL increases and future disability progression,” Dr. Fox said. “It is quite likely that the elevations in NfL seen here are reflective of new MRI disease activity, which frequently is seen without symptoms of an MS relapse,” he said

The study was funded by the Westridge Foundation, F. Hoffmann–La Roche, the Fishman Family, the Swiss National Research Foundation, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the Valhalla Foundation. Dr. Abdelhak reported receiving grants from the German Multiple Sclerosis Society and the Weill Institute for Neurosciences outside the submitted work. Dr. Kuhle has received grants from Swiss MS Society, the Swiss National Research Foundation, the Progressive MS Alliance, Biogen, Merck, Celgene, Bristol-Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and the University of Basel outside the submitted work. Dr. Fox reported receiving consulting fees from Siemens and Roche.

A version of this article appeared on Medscape.com.

A blood test that measures elevations in neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS) could warn of worsening disability up to 2 years before it occurs, a new study suggests.

Rising NfL levels are a known indicator of neuroaxonal injury and correlate with MS disease activity. Levels rise in the presence of an MS relapse or MRI activity and fall following treatment with disease-modifying therapies. But the link between NfL levels and worsening disability was less understood.

This new analysis of NfL in two large MS cohorts found that elevated levels of the neuronal protein at baseline were associated with large increases in future disability risk, even in patients with no clinical relapse.

“This rising of NfL up to 2 years before signs of disability worsening represents the window when interventions may prevent worsening,” lead investigator Ahmed Abdelhak, MD, department of neurology, University of California, San Francisco, said in a press release.

The findings were published online in JAMA Neurology.
 

Early warning system?

The study included data on 1,899 patients with nearly 13,000 patient visits from two observational, long-term, real-world cohorts: the U.S.-based Expression, Proteomics, Imaging, Clinical (EPIC) study (n = 609 patients), and the Swiss Multiple Sclerosis Cohort trial (SMSC; n = 1,290 patients).

Investigators analyzed longitudinal serum NfL measurements in conjunction with clinical disability worsening, defined as 6 months or more of increased impairment as measured by the Expanded Disability Status Scale.

Researchers also assessed the temporal association between NfL measurements and the risk of increased disability and distinguished between disability with and without relapse.

Worsening disability was reported in 227 patients in the EPIC group and 435 in the SMSC trial.

Elevated NfL at baseline was associated with a 70% higher risk for worsening disability with relapse about 11 months later in the SMSC study (hazard ratio, 1.70; P = .02). In the EPIC trial, there was trend toward a 91% higher risk for worsening disability with relapse at 12.6 months, although the findings did not meet statistical significance (HR, 1.91; P = .07).

The risk of future disability progression independent of clinical relapse was 40% higher in those with high NfL at baseline in the EPIC study 12 months after baseline (HR, 1.40; P = .02) and 49% higher in the SMSC trial 21 months later (HR, 1.49; P < .001).

The early elevation of NfL levels suggests a slower degradation of nerve cells and could be a possible early warning system of future progression of disability, allowing time for interventions that could slow or even halt further disability.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” senior author Jens Kuhle, MD, PhD, leader of the Swiss cohort and head of the Multiple Sclerosis Center at University Hospital and University of Basel, said in a statement.
 

Challenges for clinicians

Commenting on the findings, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research, Neurological Institute, Cleveland Clinic, said that, while there is a clinical test to measure NfL levels, incorporating that test into standard of care isn’t straightforward.

“The challenge for the practicing clinician is to translate these population-level studies to individual patient management decisions,” said Dr. Fox, who was not a part of the study.

“The published prediction curves corrected for age, sex, disease course, disease-modifying treatment, relapse within the past 90 days, and current disability status, the combination of which makes it rather challenging to calculate and interpret adjusted z score NfL levels in routine practice and then use it in clinical decision-making.”

The investigators said the study underscores the importance of NfL as an MS biomarker and “points to the existence of different windows of dynamic central nervous system pathology” that precedes worsening disability with or without relapse. But there may be a simpler explanation, Dr. Fox suggested.

“We know MRI activity occurs 5-10 times more frequently than relapses, and we know that MRI activity is associated with both NfL increases and future disability progression,” Dr. Fox said. “It is quite likely that the elevations in NfL seen here are reflective of new MRI disease activity, which frequently is seen without symptoms of an MS relapse,” he said

The study was funded by the Westridge Foundation, F. Hoffmann–La Roche, the Fishman Family, the Swiss National Research Foundation, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the Valhalla Foundation. Dr. Abdelhak reported receiving grants from the German Multiple Sclerosis Society and the Weill Institute for Neurosciences outside the submitted work. Dr. Kuhle has received grants from Swiss MS Society, the Swiss National Research Foundation, the Progressive MS Alliance, Biogen, Merck, Celgene, Bristol-Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and the University of Basel outside the submitted work. Dr. Fox reported receiving consulting fees from Siemens and Roche.

A version of this article appeared on Medscape.com.

TOPLINE:

People who report frequently adding salt to their food are at significantly greater risk of developing type 2 diabetes (T2D), even after adjustment for confounding factors.

METHODOLOGY:

• Researchers identified 402,982 participants in the UK Biobank from March 2006 to October 2010 who had completed a questionnaire about the frequency with which they added salt to food and who did not have diabetes, chronic kidney disease, cancer, or cardiovascular disease at baseline.
• Urine samples were collected at baseline, sodium and potassium levels were measured, and 24-hour sodium excretion was estimated.
• Investigators followed participants from baseline to diagnosis of diabetes, death, or the censoring date (May 23, 2021), whichever occurred first. Information on T2D events were collected through medical history linkage to data on hospital admissions, questionnaire, and the death register.

TAKEAWAY:

• During a mean follow-up of 11.9 years, 13,120 incident cases of T2D were documented.
• Compared with people who reported “never/rarely” adding salt to food, the sex- and age-adjusted hazard ratios (HRs) for developing T2D were 1.20, 1.32, and 1.86 for those who reported “sometimes,” “usually,” and “always” adding salt, respectively (P-trend < .001).
• After further adjustment for the Townsend deprivation index, education level, income, smoking, drinking, physical activity, and high cholesterol, the association was attenuated but remained significant, with HRs of 1.11, 1.18, and 1.28 for “sometimes,” “usually,” and “always” responses, respectively (P-trend < .001).
• After full adjustment, there was also a dose-dependent relationship across quintiles of urinary sodium and higher T2D risk, with HRs of 1 (reference), 1.12, 1.17, 1.28, and 1.34 for quintiles 2-5, respectively (P-trend < .001).
• Body fat percentage and body fat mass significantly mediated the association of adding salt with T2D, by estimated effects of 37.9% and 39.9%, respectively (both P < .001).

IN PRACTICE:

“These findings provide support that reduction of adding salt to foods may act as a potential behavioral intervention approach for preventing T2D. Future clinical trials are needed to further validate our findings,” the authors wrote.

SOURCE:

The study by Xuan Wang, MD, PhD, department of epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, and colleagues was published in the November 2023 issue of Mayo Clinic Proceedings.

LIMITATIONS:

The researchers could not completely exclude the possibility that high frequency of adding salt to foods is a marker for an unhealthy lifestyle. Self-reported frequency of adding salt to food might be subject to information bias and did not provide quantitative information on total sodium intake. In addition, participants were mainly of European descent, making application of the findings to other ethnic groups unclear; the observational design meant researchers could not rule out residual confounding; and information on addition of salt to food was available only at baseline, so potential changes in salt consumption during follow-up could not be considered.

DISCLOSURES:

The study was supported by grants from the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the Fogarty International Center; and Tulane Research Centers of Excellence Awards. The authors reported no potential competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

People who report frequently adding salt to their food are at significantly greater risk of developing type 2 diabetes (T2D), even after adjustment for confounding factors.

METHODOLOGY:

• Researchers identified 402,982 participants in the UK Biobank from March 2006 to October 2010 who had completed a questionnaire about the frequency with which they added salt to food and who did not have diabetes, chronic kidney disease, cancer, or cardiovascular disease at baseline.
• Urine samples were collected at baseline, sodium and potassium levels were measured, and 24-hour sodium excretion was estimated.
• Investigators followed participants from baseline to diagnosis of diabetes, death, or the censoring date (May 23, 2021), whichever occurred first. Information on T2D events were collected through medical history linkage to data on hospital admissions, questionnaire, and the death register.

TAKEAWAY:

• During a mean follow-up of 11.9 years, 13,120 incident cases of T2D were documented.
• Compared with people who reported “never/rarely” adding salt to food, the sex- and age-adjusted hazard ratios (HRs) for developing T2D were 1.20, 1.32, and 1.86 for those who reported “sometimes,” “usually,” and “always” adding salt, respectively (P-trend < .001).
• After further adjustment for the Townsend deprivation index, education level, income, smoking, drinking, physical activity, and high cholesterol, the association was attenuated but remained significant, with HRs of 1.11, 1.18, and 1.28 for “sometimes,” “usually,” and “always” responses, respectively (P-trend < .001).
• After full adjustment, there was also a dose-dependent relationship across quintiles of urinary sodium and higher T2D risk, with HRs of 1 (reference), 1.12, 1.17, 1.28, and 1.34 for quintiles 2-5, respectively (P-trend < .001).
• Body fat percentage and body fat mass significantly mediated the association of adding salt with T2D, by estimated effects of 37.9% and 39.9%, respectively (both P < .001).

IN PRACTICE:

“These findings provide support that reduction of adding salt to foods may act as a potential behavioral intervention approach for preventing T2D. Future clinical trials are needed to further validate our findings,” the authors wrote.

SOURCE:

The study by Xuan Wang, MD, PhD, department of epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, and colleagues was published in the November 2023 issue of Mayo Clinic Proceedings.

LIMITATIONS:

The researchers could not completely exclude the possibility that high frequency of adding salt to foods is a marker for an unhealthy lifestyle. Self-reported frequency of adding salt to food might be subject to information bias and did not provide quantitative information on total sodium intake. In addition, participants were mainly of European descent, making application of the findings to other ethnic groups unclear; the observational design meant researchers could not rule out residual confounding; and information on addition of salt to food was available only at baseline, so potential changes in salt consumption during follow-up could not be considered.

DISCLOSURES:

The study was supported by grants from the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the Fogarty International Center; and Tulane Research Centers of Excellence Awards. The authors reported no potential competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

People who report frequently adding salt to their food are at significantly greater risk of developing type 2 diabetes (T2D), even after adjustment for confounding factors.

METHODOLOGY:

• Researchers identified 402,982 participants in the UK Biobank from March 2006 to October 2010 who had completed a questionnaire about the frequency with which they added salt to food and who did not have diabetes, chronic kidney disease, cancer, or cardiovascular disease at baseline.
• Urine samples were collected at baseline, sodium and potassium levels were measured, and 24-hour sodium excretion was estimated.
• Investigators followed participants from baseline to diagnosis of diabetes, death, or the censoring date (May 23, 2021), whichever occurred first. Information on T2D events were collected through medical history linkage to data on hospital admissions, questionnaire, and the death register.

TAKEAWAY:

• During a mean follow-up of 11.9 years, 13,120 incident cases of T2D were documented.
• Compared with people who reported “never/rarely” adding salt to food, the sex- and age-adjusted hazard ratios (HRs) for developing T2D were 1.20, 1.32, and 1.86 for those who reported “sometimes,” “usually,” and “always” adding salt, respectively (P-trend < .001).
• After further adjustment for the Townsend deprivation index, education level, income, smoking, drinking, physical activity, and high cholesterol, the association was attenuated but remained significant, with HRs of 1.11, 1.18, and 1.28 for “sometimes,” “usually,” and “always” responses, respectively (P-trend < .001).
• After full adjustment, there was also a dose-dependent relationship across quintiles of urinary sodium and higher T2D risk, with HRs of 1 (reference), 1.12, 1.17, 1.28, and 1.34 for quintiles 2-5, respectively (P-trend < .001).
• Body fat percentage and body fat mass significantly mediated the association of adding salt with T2D, by estimated effects of 37.9% and 39.9%, respectively (both P < .001).

IN PRACTICE:

“These findings provide support that reduction of adding salt to foods may act as a potential behavioral intervention approach for preventing T2D. Future clinical trials are needed to further validate our findings,” the authors wrote.

SOURCE:

The study by Xuan Wang, MD, PhD, department of epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, and colleagues was published in the November 2023 issue of Mayo Clinic Proceedings.

LIMITATIONS:

The researchers could not completely exclude the possibility that high frequency of adding salt to foods is a marker for an unhealthy lifestyle. Self-reported frequency of adding salt to food might be subject to information bias and did not provide quantitative information on total sodium intake. In addition, participants were mainly of European descent, making application of the findings to other ethnic groups unclear; the observational design meant researchers could not rule out residual confounding; and information on addition of salt to food was available only at baseline, so potential changes in salt consumption during follow-up could not be considered.

DISCLOSURES:

The study was supported by grants from the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the Fogarty International Center; and Tulane Research Centers of Excellence Awards. The authors reported no potential competing interests.

A version of this article appeared on Medscape.com.

Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.

But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.

“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.

Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” Dr. Kaye said.
 

Thank COVID?

Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.

Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.

Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.

RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.

Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.

“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.

“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
 

Hope for Dravet syndrome

Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.

Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.

The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.

“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.

Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.

“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.

“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.

“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
 

A promising future

Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”

And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.

Take, for example, a case reported recently in the New England Journal of Medicine.

Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.

One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.

However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”

“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.

The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.

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

Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.

But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.

“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.

Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” Dr. Kaye said.
 

Thank COVID?

Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.

Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.

Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.

RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.

Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.

“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.

“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
 

Hope for Dravet syndrome

Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.

Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.

The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.

“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.

Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.

“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.

“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.

“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
 

A promising future

Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”

And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.

Take, for example, a case reported recently in the New England Journal of Medicine.

Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.

One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.

However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”

“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.

The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.

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

Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.

But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.

“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.

Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” Dr. Kaye said.
 

Thank COVID?

Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.

Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.

Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.

RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.

Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.

“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.

“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
 

Hope for Dravet syndrome

Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.

Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.

The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.

“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.

Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.

“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.

“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.

“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
 

A promising future

Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”

And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.

Take, for example, a case reported recently in the New England Journal of Medicine.

Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.

One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.

However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”

“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.

The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.

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

TOPLINE:

Among patients with colorectal cancer (CRC), those with complicated diabetes were at higher risk of poor survival than their peers without diabetes, while those with uncomplicated diabetes had insignificantly worse cancer outcomes.

METHODOLOGY:

• This population-based retrospective cohort study used 2007-2015 data from the Taiwan Cancer Registry, which is linked to national insurance and death registry data.
• The analysis included 59,202 adults with stage I-III CRC who underwent potentially curative surgery: 44,944 without diabetes, 8,864 with uncomplicated diabetes, and 5,394 with complicated diabetes.
• The association between diabetes severity and CRC survival, overall survival (OS), disease-free survival (DFS), time to recurrence, and cancer-specific survival (CSS) was examined.
•  

TAKEAWAY:

• Patients with uncomplicated diabetes had insignificantly worse OS (hazard ratio, 1.05), DFS (HR, 1.08), and CSS (HR, 0.98), compared with peers who did not have diabetes.
• Patients with complicated diabetes were at significantly higher risk of poor OS (HR, 1.85), DFS (HR, 1.75), and CSS (HR, 1.41), compared with those without diabetes.
• Patients with diabetes were also at higher risk for CRC recurrence than those without diabetes.
• Except for recurrence risk, the impact of complicated diabetes on CRC survival – that is, OS, DFS, and CSS – was more pronounced among women and those with early-stage cancer.

IN PRACTICE:

“These findings indicate that preventing diabetes complications may help improve survival in patients with CRC, especially [in] female patients and those in the early stages of the disease. Thus, a multidisciplinary approach is recommended for patients with CRC,” the authors conclude.

SOURCE:

The study, with first author Hsin-Yin Hsu, MD, National Taiwan University, Taipei, was published online in the journal Cancer.

LIMITATIONS:

Only patients from Taiwan were included, which limits generalizability, because CRC prognosis may vary in accordance with race or cancer treatment strategy – factors that may differ among countries. Data on glucose levels and diabetes duration were unavailable, potentially leading to misclassification of diabetes status.

DISCLOSURES:

Funding was provided by the Ministry of Science and Technology and the Ministry of Health and Welfare. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Among patients with colorectal cancer (CRC), those with complicated diabetes were at higher risk of poor survival than their peers without diabetes, while those with uncomplicated diabetes had insignificantly worse cancer outcomes.

METHODOLOGY:

• This population-based retrospective cohort study used 2007-2015 data from the Taiwan Cancer Registry, which is linked to national insurance and death registry data.
• The analysis included 59,202 adults with stage I-III CRC who underwent potentially curative surgery: 44,944 without diabetes, 8,864 with uncomplicated diabetes, and 5,394 with complicated diabetes.
• The association between diabetes severity and CRC survival, overall survival (OS), disease-free survival (DFS), time to recurrence, and cancer-specific survival (CSS) was examined.
•  

TAKEAWAY:

• Patients with uncomplicated diabetes had insignificantly worse OS (hazard ratio, 1.05), DFS (HR, 1.08), and CSS (HR, 0.98), compared with peers who did not have diabetes.
• Patients with complicated diabetes were at significantly higher risk of poor OS (HR, 1.85), DFS (HR, 1.75), and CSS (HR, 1.41), compared with those without diabetes.
• Patients with diabetes were also at higher risk for CRC recurrence than those without diabetes.
• Except for recurrence risk, the impact of complicated diabetes on CRC survival – that is, OS, DFS, and CSS – was more pronounced among women and those with early-stage cancer.

IN PRACTICE:

“These findings indicate that preventing diabetes complications may help improve survival in patients with CRC, especially [in] female patients and those in the early stages of the disease. Thus, a multidisciplinary approach is recommended for patients with CRC,” the authors conclude.

SOURCE:

The study, with first author Hsin-Yin Hsu, MD, National Taiwan University, Taipei, was published online in the journal Cancer.

LIMITATIONS:

Only patients from Taiwan were included, which limits generalizability, because CRC prognosis may vary in accordance with race or cancer treatment strategy – factors that may differ among countries. Data on glucose levels and diabetes duration were unavailable, potentially leading to misclassification of diabetes status.

DISCLOSURES:

Funding was provided by the Ministry of Science and Technology and the Ministry of Health and Welfare. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Among patients with colorectal cancer (CRC), those with complicated diabetes were at higher risk of poor survival than their peers without diabetes, while those with uncomplicated diabetes had insignificantly worse cancer outcomes.

METHODOLOGY:

• This population-based retrospective cohort study used 2007-2015 data from the Taiwan Cancer Registry, which is linked to national insurance and death registry data.
• The analysis included 59,202 adults with stage I-III CRC who underwent potentially curative surgery: 44,944 without diabetes, 8,864 with uncomplicated diabetes, and 5,394 with complicated diabetes.
• The association between diabetes severity and CRC survival, overall survival (OS), disease-free survival (DFS), time to recurrence, and cancer-specific survival (CSS) was examined.
•  

TAKEAWAY:

• Patients with uncomplicated diabetes had insignificantly worse OS (hazard ratio, 1.05), DFS (HR, 1.08), and CSS (HR, 0.98), compared with peers who did not have diabetes.
• Patients with complicated diabetes were at significantly higher risk of poor OS (HR, 1.85), DFS (HR, 1.75), and CSS (HR, 1.41), compared with those without diabetes.
• Patients with diabetes were also at higher risk for CRC recurrence than those without diabetes.
• Except for recurrence risk, the impact of complicated diabetes on CRC survival – that is, OS, DFS, and CSS – was more pronounced among women and those with early-stage cancer.

IN PRACTICE:

“These findings indicate that preventing diabetes complications may help improve survival in patients with CRC, especially [in] female patients and those in the early stages of the disease. Thus, a multidisciplinary approach is recommended for patients with CRC,” the authors conclude.

SOURCE:

The study, with first author Hsin-Yin Hsu, MD, National Taiwan University, Taipei, was published online in the journal Cancer.

LIMITATIONS:

Only patients from Taiwan were included, which limits generalizability, because CRC prognosis may vary in accordance with race or cancer treatment strategy – factors that may differ among countries. Data on glucose levels and diabetes duration were unavailable, potentially leading to misclassification of diabetes status.

DISCLOSURES:

Funding was provided by the Ministry of Science and Technology and the Ministry of Health and Welfare. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Childhood trauma increases the risk of developing a primary headache disorder in adulthood, with more early adverse experiences raising the risk even more, a new study found.

METHODOLOGY:

• The meta-analysis included 28 observational studies with 154,739 persons in 19 countries that assessed the relationship between at least one adverse childhood experience (ACE) and primary headache (including migraine, tension-type headache, cluster headache, and chronic/severe headache) at age 21 years or older.
• From each study, researchers extracted outcome point estimates and corresponding 95% confidence intervals, number of events in each group, and covariates included in the model. They subcategorized ACEs according to those involving threat (for example, physical, emotional, or sexual abuse) and deprivation (for example, neglect, household substance misuse).
• For the primary analysis, the researchers calculated the odds ratios and hazard ratios of headache among persons with at least one ACE, compared with those with no ACEs.
• They also tested an underlying biological theory that threat and deprivation ACEs may manifest differently in neurodevelopment, with distinct impacts on primary headaches.
•  

TAKEAWAY:

• The most commonly reported ACEs were physical abuse (77%), sexual abuse (73%), and exposure to family violence (38%).
• Compared with having experienced no ACEs, experiencing at least one was associated with primary headaches (pooled OR, 1.48; 95% confidence interval, 1.36-1.61).
• As the number of ACEs increased, the strength of the association with primary headaches increased in a dose-response relationship (P for trend < .0001).
• Both threat and deprivation were independently associated with primary headaches; the pooled main effect was consistent for threat (OR, 1.46; 95% CI, 1.32-1.60) and for deprivation (OR, 1.35; 95% CI, 1.23-1.49), suggesting possible distinct pathways of early adversity.
•  

IN PRACTICE:

Clinicians who treat primary headaches in adults “should routinely screen for ACEs, educate patients on the connection between ACEs and health, and provide referrals for treatment strategies,” the investigators write. Strategies such as trauma-informed or attachment-based therapy may help rewire parts of the brain that have been dysregulated, they add.

SOURCE:

The study was led by Claudia Sikorski, department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont. It was published online in Neurology.

LIMITATIONS:

The findings reflect a conservative estimate of the true impact of ACEs on primary headaches, because ACEs are commonly underreported. The analysis could not statistically disentangle younger adults with developing brains (age 21-26 years) from older adults. Not all included studies adjusted for age and sex, which are known risk factors for headaches. The study did not explore the relationship between ACEs and primary headache disorders in childhood and adolescence. Owing to the inherent nature of studies investigating ACEs, causation cannot be inferred.

DISCLOSURES:

The authors report no targeted funding and no relevant conflicts of interest.

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

TOPLINE:

Childhood trauma increases the risk of developing a primary headache disorder in adulthood, with more early adverse experiences raising the risk even more, a new study found.

METHODOLOGY:

• The meta-analysis included 28 observational studies with 154,739 persons in 19 countries that assessed the relationship between at least one adverse childhood experience (ACE) and primary headache (including migraine, tension-type headache, cluster headache, and chronic/severe headache) at age 21 years or older.
• From each study, researchers extracted outcome point estimates and corresponding 95% confidence intervals, number of events in each group, and covariates included in the model. They subcategorized ACEs according to those involving threat (for example, physical, emotional, or sexual abuse) and deprivation (for example, neglect, household substance misuse).
• For the primary analysis, the researchers calculated the odds ratios and hazard ratios of headache among persons with at least one ACE, compared with those with no ACEs.
• They also tested an underlying biological theory that threat and deprivation ACEs may manifest differently in neurodevelopment, with distinct impacts on primary headaches.
•  

TAKEAWAY:

• The most commonly reported ACEs were physical abuse (77%), sexual abuse (73%), and exposure to family violence (38%).
• Compared with having experienced no ACEs, experiencing at least one was associated with primary headaches (pooled OR, 1.48; 95% confidence interval, 1.36-1.61).
• As the number of ACEs increased, the strength of the association with primary headaches increased in a dose-response relationship (P for trend < .0001).
• Both threat and deprivation were independently associated with primary headaches; the pooled main effect was consistent for threat (OR, 1.46; 95% CI, 1.32-1.60) and for deprivation (OR, 1.35; 95% CI, 1.23-1.49), suggesting possible distinct pathways of early adversity.
•  

IN PRACTICE:

Clinicians who treat primary headaches in adults “should routinely screen for ACEs, educate patients on the connection between ACEs and health, and provide referrals for treatment strategies,” the investigators write. Strategies such as trauma-informed or attachment-based therapy may help rewire parts of the brain that have been dysregulated, they add.

SOURCE:

The study was led by Claudia Sikorski, department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont. It was published online in Neurology.

LIMITATIONS:

The findings reflect a conservative estimate of the true impact of ACEs on primary headaches, because ACEs are commonly underreported. The analysis could not statistically disentangle younger adults with developing brains (age 21-26 years) from older adults. Not all included studies adjusted for age and sex, which are known risk factors for headaches. The study did not explore the relationship between ACEs and primary headache disorders in childhood and adolescence. Owing to the inherent nature of studies investigating ACEs, causation cannot be inferred.

DISCLOSURES:

The authors report no targeted funding and no relevant conflicts of interest.

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

TOPLINE:

Childhood trauma increases the risk of developing a primary headache disorder in adulthood, with more early adverse experiences raising the risk even more, a new study found.

METHODOLOGY:

• The meta-analysis included 28 observational studies with 154,739 persons in 19 countries that assessed the relationship between at least one adverse childhood experience (ACE) and primary headache (including migraine, tension-type headache, cluster headache, and chronic/severe headache) at age 21 years or older.
• From each study, researchers extracted outcome point estimates and corresponding 95% confidence intervals, number of events in each group, and covariates included in the model. They subcategorized ACEs according to those involving threat (for example, physical, emotional, or sexual abuse) and deprivation (for example, neglect, household substance misuse).
• For the primary analysis, the researchers calculated the odds ratios and hazard ratios of headache among persons with at least one ACE, compared with those with no ACEs.
• They also tested an underlying biological theory that threat and deprivation ACEs may manifest differently in neurodevelopment, with distinct impacts on primary headaches.
•  

TAKEAWAY:

• The most commonly reported ACEs were physical abuse (77%), sexual abuse (73%), and exposure to family violence (38%).
• Compared with having experienced no ACEs, experiencing at least one was associated with primary headaches (pooled OR, 1.48; 95% confidence interval, 1.36-1.61).
• As the number of ACEs increased, the strength of the association with primary headaches increased in a dose-response relationship (P for trend < .0001).
• Both threat and deprivation were independently associated with primary headaches; the pooled main effect was consistent for threat (OR, 1.46; 95% CI, 1.32-1.60) and for deprivation (OR, 1.35; 95% CI, 1.23-1.49), suggesting possible distinct pathways of early adversity.
•  

IN PRACTICE:

Clinicians who treat primary headaches in adults “should routinely screen for ACEs, educate patients on the connection between ACEs and health, and provide referrals for treatment strategies,” the investigators write. Strategies such as trauma-informed or attachment-based therapy may help rewire parts of the brain that have been dysregulated, they add.

SOURCE:

The study was led by Claudia Sikorski, department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont. It was published online in Neurology.

LIMITATIONS:

The findings reflect a conservative estimate of the true impact of ACEs on primary headaches, because ACEs are commonly underreported. The analysis could not statistically disentangle younger adults with developing brains (age 21-26 years) from older adults. Not all included studies adjusted for age and sex, which are known risk factors for headaches. The study did not explore the relationship between ACEs and primary headache disorders in childhood and adolescence. Owing to the inherent nature of studies investigating ACEs, causation cannot be inferred.

DISCLOSURES:

The authors report no targeted funding and no relevant conflicts of interest.

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

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

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

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

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

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

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

Studies have shown links between statin use and type 2 diabetes (T2D) for more than a decade. A U.S. Food and Drug Administration label change for the drugs warned in 2012 about reports of increased risks of high blood glucose and glycosylated hemoglobin (A1c) levels. However, in the same warning, the FDA said it “continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.”

Indeed, although the warning triggered much discussion at the time and a number of meta-analyses and other observational studies in more recent years, that conclusion seems to hold among clinicians and society guidelines.

For example, in a recent practice pointer on the risk of diabetes with statins published in the BMJ, Ishak Mansi, MD, of the Orlando VA Health Care System, and colleagues write, “This potential adverse effect of diabetes with statin use should not be a barrier to starting statin treatment when indicated.”

They also called for further research to answer such questions as, “Is statin-associated diabetes reversible upon statin discontinuation? Would intermittent use minimize this risk while maintaining cardiovascular benefits?”

An earlier study among individuals at high risk for diabetes found significantly higher rates of incident diabetes at 10 years among patients on placebo, metformin, or lifestyle intervention who also initiated statin therapy. Jill Crandall, MD, Albert Einstein College of Medicine, New York, and colleagues conclude, “For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment.”

In the same vein, a recent review by Byron Hoogwerf, MD, Emeritus, department of endocrinology, diabetes, and metabolism, Cleveland Clinic, is titled, “Statins may increase diabetes, but benefit still outweighs risk.”
 

Rosuvastatin versus Atorvastatin

The latest study in this arena is an analysis of the LODESTAR randomized controlled trial of 4,400 patients with coronary artery disease in 12 hospitals in Korea which compares the risks associated with individual statins.

Senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Severance Cardiovascular Hospital, Seoul, South Korea, said in an interview that the study was prompted by the “limited” studies evaluating clinical outcomes, including diabetes risk, according to statin type.

Dr. Hong and colleagues compared the risk of developing diabetes among those taking rosuvastatin (mean daily dose, 17.1 mg) or atorvastatin (mean daily dose 36 mg) for 3 years. While both statins effectively prevented myocardial infarction, stroke, and death, those taking rosuvastatin had a higher incidence of new-onset T2D requiring initiation of antidiabetic drugs (7.2% vs. 5.3%; hazard ratio, 1.39) and cataract surgery (2.5% vs. 1.5%; HR, 1.66).

Overall, the HR of new-onset T2D was 1.29 (95% confidence interval, 1.01-1.63; P = .04).

“The percentages of new-onset diabetes and cataract are in line with previous studies regarding statin therapy in patients with atherosclerotic cardiovascular disease,” Dr. Hong said. “Additional research specifically focusing on these outcomes is required, with more frequent measurement of glucose and A1c levels to detect new-onset diabetes and regular ophthalmologic examinations to detect cataracts.”

“However,” he added, “when using rosuvastatin over atorvastatin, we ... emphasize the importance of meticulous monitoring and appropriate lifestyle interventions to mitigate the risk of new-onset diabetes or cataracts.”

Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute, was not convinced, and said the study “does not provide useful insights into the use of these drugs.”

The investigators used whatever dose they wanted, “and the authors report only the median dose after 3 years,” he said in an interview. “Because there was a slightly greater reduction in low-density lipoprotein (LDL) cholesterol with rosuvastatin, the relative dose was actually higher.”

“We know that new-onset diabetes with statins is dose-dependent,” he said. “The P-values for diabetes incidence were marginal (very close to P = .05). Accordingly, the diabetes data are unconvincing. ... The similar efficacy is not surprising given the open-label dosing with relatively similar effects on lipids.”

Seth Shay Martin, MD, MHS, director of the Advanced Lipid Disorders Program and Digital Health Lab, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, also commented on the results. The findings are “in line with existing knowledge and current guidelines,” he said. “Therefore, the study should not influence prescribing.”

“Although the study suggests that rosuvastatin was associated with a higher risk of new-onset diabetes mellitus requiring antidiabetics and cataract surgery, compared with atorvastatin, these findings should be interpreted with caution given the open-label nature of the study and require further investigation,” he said.

“The mean daily doses of statins were somewhat below target for secondary prevention,” he noted. “Ideally, patients with coronary artery disease (CAD) take 20-40 mg daily of rosuvastatin or 40-80 mg daily of atorvastatin.”

“Furthermore, the LDL cholesterol levels were not optimized in the patients,” he said. “The mean LDL-C was 1.8-1.9 mmol/L, which is equivalent to 70-73 mg/dL. In the current treatment era, we generally treat to LDL-C levels less than 70 mg/dL and often less than 55 mg/dL in CAD patients.”

“The cataracts finding is particularly odd,” he added. “There was historic concern for cataracts with statin therapy, initially because of studies in beagle dogs. However, high-quality evidence from statin trials has not shown a risk for cataracts.” 

So which statin has the lowest risk of triggering new-onset diabetes? As Dr. Hong noted, the literature is sparse when it comes to comparing the risk among specific statins. Some studies suggest that the risk may depend on the individual and their specific risk factors, as well as the dose and intensity of the prescribed statin.

One recent study suggests that while the overall chance of developing diabetes is small, when looking at risk by years of exposure, atorvastatin, rosuvastatin, and lovastatin carried the largest risk, whereas the risk was lower with pravastatin and simvastatin.

Risks also seemed lower with fluvastatin and pitavastatin, but there were too few study patients taking those drugs long-term to include in the subanalysis.

With input from the latest guidelines from the American Heart Association and the American Diabetes Association, as well as findings from a clinical guide on statin-associated diabetes, Dr. Hoogwerf suggests in his review that shared decision-making before starting statin therapy of any type include the following considerations/discussion points:

• For all patients: Screening to determine baseline glycemic status; nonstatin therapies to lower cholesterol; and variables associated with an increased risk of diabetes, including antihypertensive drugs.
• For patients without T2D: The possibility of developing T2D, types and doses of statins, and the fact that statin benefits “generally far outweigh” risks of developing diabetes.
• For patients with T2D: Possible small adverse effects on glycemic control; statin benefits in reducing risk for atherosclerotic cardiovascular disease, which “significantly outweigh” the small increase in A1c; and mitigation of adverse glycemic effects of statins with glucose-lowering therapies.

It’s worth noting that the AHA and ADA guidelines, among others, also emphasize that such discussions should include the importance of weight loss, regular exercise, and adhering to a healthy lifestyle to mitigate risks of both diabetes and heart disease, with or without statins.

Dr. Hong, Dr. Nissen, and Dr. Martin report no relevant financial relationships. Dr. Hoogwerf has disclosed ownership interest in Eli Lilly and consulting for MannKind and Zealand Pharmaceuticals.

A version of this article appeared on Medscape.com.

Studies have shown links between statin use and type 2 diabetes (T2D) for more than a decade. A U.S. Food and Drug Administration label change for the drugs warned in 2012 about reports of increased risks of high blood glucose and glycosylated hemoglobin (A1c) levels. However, in the same warning, the FDA said it “continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.”

Indeed, although the warning triggered much discussion at the time and a number of meta-analyses and other observational studies in more recent years, that conclusion seems to hold among clinicians and society guidelines.

For example, in a recent practice pointer on the risk of diabetes with statins published in the BMJ, Ishak Mansi, MD, of the Orlando VA Health Care System, and colleagues write, “This potential adverse effect of diabetes with statin use should not be a barrier to starting statin treatment when indicated.”

They also called for further research to answer such questions as, “Is statin-associated diabetes reversible upon statin discontinuation? Would intermittent use minimize this risk while maintaining cardiovascular benefits?”

An earlier study among individuals at high risk for diabetes found significantly higher rates of incident diabetes at 10 years among patients on placebo, metformin, or lifestyle intervention who also initiated statin therapy. Jill Crandall, MD, Albert Einstein College of Medicine, New York, and colleagues conclude, “For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment.”

In the same vein, a recent review by Byron Hoogwerf, MD, Emeritus, department of endocrinology, diabetes, and metabolism, Cleveland Clinic, is titled, “Statins may increase diabetes, but benefit still outweighs risk.”
 

Rosuvastatin versus Atorvastatin

The latest study in this arena is an analysis of the LODESTAR randomized controlled trial of 4,400 patients with coronary artery disease in 12 hospitals in Korea which compares the risks associated with individual statins.

Senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Severance Cardiovascular Hospital, Seoul, South Korea, said in an interview that the study was prompted by the “limited” studies evaluating clinical outcomes, including diabetes risk, according to statin type.

Dr. Hong and colleagues compared the risk of developing diabetes among those taking rosuvastatin (mean daily dose, 17.1 mg) or atorvastatin (mean daily dose 36 mg) for 3 years. While both statins effectively prevented myocardial infarction, stroke, and death, those taking rosuvastatin had a higher incidence of new-onset T2D requiring initiation of antidiabetic drugs (7.2% vs. 5.3%; hazard ratio, 1.39) and cataract surgery (2.5% vs. 1.5%; HR, 1.66).

Overall, the HR of new-onset T2D was 1.29 (95% confidence interval, 1.01-1.63; P = .04).

“The percentages of new-onset diabetes and cataract are in line with previous studies regarding statin therapy in patients with atherosclerotic cardiovascular disease,” Dr. Hong said. “Additional research specifically focusing on these outcomes is required, with more frequent measurement of glucose and A1c levels to detect new-onset diabetes and regular ophthalmologic examinations to detect cataracts.”

“However,” he added, “when using rosuvastatin over atorvastatin, we ... emphasize the importance of meticulous monitoring and appropriate lifestyle interventions to mitigate the risk of new-onset diabetes or cataracts.”

Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute, was not convinced, and said the study “does not provide useful insights into the use of these drugs.”

The investigators used whatever dose they wanted, “and the authors report only the median dose after 3 years,” he said in an interview. “Because there was a slightly greater reduction in low-density lipoprotein (LDL) cholesterol with rosuvastatin, the relative dose was actually higher.”

“We know that new-onset diabetes with statins is dose-dependent,” he said. “The P-values for diabetes incidence were marginal (very close to P = .05). Accordingly, the diabetes data are unconvincing. ... The similar efficacy is not surprising given the open-label dosing with relatively similar effects on lipids.”

Seth Shay Martin, MD, MHS, director of the Advanced Lipid Disorders Program and Digital Health Lab, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, also commented on the results. The findings are “in line with existing knowledge and current guidelines,” he said. “Therefore, the study should not influence prescribing.”

“Although the study suggests that rosuvastatin was associated with a higher risk of new-onset diabetes mellitus requiring antidiabetics and cataract surgery, compared with atorvastatin, these findings should be interpreted with caution given the open-label nature of the study and require further investigation,” he said.

“The mean daily doses of statins were somewhat below target for secondary prevention,” he noted. “Ideally, patients with coronary artery disease (CAD) take 20-40 mg daily of rosuvastatin or 40-80 mg daily of atorvastatin.”

“Furthermore, the LDL cholesterol levels were not optimized in the patients,” he said. “The mean LDL-C was 1.8-1.9 mmol/L, which is equivalent to 70-73 mg/dL. In the current treatment era, we generally treat to LDL-C levels less than 70 mg/dL and often less than 55 mg/dL in CAD patients.”

“The cataracts finding is particularly odd,” he added. “There was historic concern for cataracts with statin therapy, initially because of studies in beagle dogs. However, high-quality evidence from statin trials has not shown a risk for cataracts.” 

So which statin has the lowest risk of triggering new-onset diabetes? As Dr. Hong noted, the literature is sparse when it comes to comparing the risk among specific statins. Some studies suggest that the risk may depend on the individual and their specific risk factors, as well as the dose and intensity of the prescribed statin.

One recent study suggests that while the overall chance of developing diabetes is small, when looking at risk by years of exposure, atorvastatin, rosuvastatin, and lovastatin carried the largest risk, whereas the risk was lower with pravastatin and simvastatin.

Risks also seemed lower with fluvastatin and pitavastatin, but there were too few study patients taking those drugs long-term to include in the subanalysis.

With input from the latest guidelines from the American Heart Association and the American Diabetes Association, as well as findings from a clinical guide on statin-associated diabetes, Dr. Hoogwerf suggests in his review that shared decision-making before starting statin therapy of any type include the following considerations/discussion points:

• For all patients: Screening to determine baseline glycemic status; nonstatin therapies to lower cholesterol; and variables associated with an increased risk of diabetes, including antihypertensive drugs.
• For patients without T2D: The possibility of developing T2D, types and doses of statins, and the fact that statin benefits “generally far outweigh” risks of developing diabetes.
• For patients with T2D: Possible small adverse effects on glycemic control; statin benefits in reducing risk for atherosclerotic cardiovascular disease, which “significantly outweigh” the small increase in A1c; and mitigation of adverse glycemic effects of statins with glucose-lowering therapies.

It’s worth noting that the AHA and ADA guidelines, among others, also emphasize that such discussions should include the importance of weight loss, regular exercise, and adhering to a healthy lifestyle to mitigate risks of both diabetes and heart disease, with or without statins.

Dr. Hong, Dr. Nissen, and Dr. Martin report no relevant financial relationships. Dr. Hoogwerf has disclosed ownership interest in Eli Lilly and consulting for MannKind and Zealand Pharmaceuticals.

A version of this article appeared on Medscape.com.

Studies have shown links between statin use and type 2 diabetes (T2D) for more than a decade. A U.S. Food and Drug Administration label change for the drugs warned in 2012 about reports of increased risks of high blood glucose and glycosylated hemoglobin (A1c) levels. However, in the same warning, the FDA said it “continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.”

Indeed, although the warning triggered much discussion at the time and a number of meta-analyses and other observational studies in more recent years, that conclusion seems to hold among clinicians and society guidelines.

For example, in a recent practice pointer on the risk of diabetes with statins published in the BMJ, Ishak Mansi, MD, of the Orlando VA Health Care System, and colleagues write, “This potential adverse effect of diabetes with statin use should not be a barrier to starting statin treatment when indicated.”

They also called for further research to answer such questions as, “Is statin-associated diabetes reversible upon statin discontinuation? Would intermittent use minimize this risk while maintaining cardiovascular benefits?”

An earlier study among individuals at high risk for diabetes found significantly higher rates of incident diabetes at 10 years among patients on placebo, metformin, or lifestyle intervention who also initiated statin therapy. Jill Crandall, MD, Albert Einstein College of Medicine, New York, and colleagues conclude, “For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment.”

In the same vein, a recent review by Byron Hoogwerf, MD, Emeritus, department of endocrinology, diabetes, and metabolism, Cleveland Clinic, is titled, “Statins may increase diabetes, but benefit still outweighs risk.”
 

Rosuvastatin versus Atorvastatin

The latest study in this arena is an analysis of the LODESTAR randomized controlled trial of 4,400 patients with coronary artery disease in 12 hospitals in Korea which compares the risks associated with individual statins.

Senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Severance Cardiovascular Hospital, Seoul, South Korea, said in an interview that the study was prompted by the “limited” studies evaluating clinical outcomes, including diabetes risk, according to statin type.

Dr. Hong and colleagues compared the risk of developing diabetes among those taking rosuvastatin (mean daily dose, 17.1 mg) or atorvastatin (mean daily dose 36 mg) for 3 years. While both statins effectively prevented myocardial infarction, stroke, and death, those taking rosuvastatin had a higher incidence of new-onset T2D requiring initiation of antidiabetic drugs (7.2% vs. 5.3%; hazard ratio, 1.39) and cataract surgery (2.5% vs. 1.5%; HR, 1.66).

Overall, the HR of new-onset T2D was 1.29 (95% confidence interval, 1.01-1.63; P = .04).

“The percentages of new-onset diabetes and cataract are in line with previous studies regarding statin therapy in patients with atherosclerotic cardiovascular disease,” Dr. Hong said. “Additional research specifically focusing on these outcomes is required, with more frequent measurement of glucose and A1c levels to detect new-onset diabetes and regular ophthalmologic examinations to detect cataracts.”

“However,” he added, “when using rosuvastatin over atorvastatin, we ... emphasize the importance of meticulous monitoring and appropriate lifestyle interventions to mitigate the risk of new-onset diabetes or cataracts.”

Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute, was not convinced, and said the study “does not provide useful insights into the use of these drugs.”

The investigators used whatever dose they wanted, “and the authors report only the median dose after 3 years,” he said in an interview. “Because there was a slightly greater reduction in low-density lipoprotein (LDL) cholesterol with rosuvastatin, the relative dose was actually higher.”

“We know that new-onset diabetes with statins is dose-dependent,” he said. “The P-values for diabetes incidence were marginal (very close to P = .05). Accordingly, the diabetes data are unconvincing. ... The similar efficacy is not surprising given the open-label dosing with relatively similar effects on lipids.”

Seth Shay Martin, MD, MHS, director of the Advanced Lipid Disorders Program and Digital Health Lab, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, also commented on the results. The findings are “in line with existing knowledge and current guidelines,” he said. “Therefore, the study should not influence prescribing.”

“Although the study suggests that rosuvastatin was associated with a higher risk of new-onset diabetes mellitus requiring antidiabetics and cataract surgery, compared with atorvastatin, these findings should be interpreted with caution given the open-label nature of the study and require further investigation,” he said.

“The mean daily doses of statins were somewhat below target for secondary prevention,” he noted. “Ideally, patients with coronary artery disease (CAD) take 20-40 mg daily of rosuvastatin or 40-80 mg daily of atorvastatin.”

“Furthermore, the LDL cholesterol levels were not optimized in the patients,” he said. “The mean LDL-C was 1.8-1.9 mmol/L, which is equivalent to 70-73 mg/dL. In the current treatment era, we generally treat to LDL-C levels less than 70 mg/dL and often less than 55 mg/dL in CAD patients.”

“The cataracts finding is particularly odd,” he added. “There was historic concern for cataracts with statin therapy, initially because of studies in beagle dogs. However, high-quality evidence from statin trials has not shown a risk for cataracts.” 

So which statin has the lowest risk of triggering new-onset diabetes? As Dr. Hong noted, the literature is sparse when it comes to comparing the risk among specific statins. Some studies suggest that the risk may depend on the individual and their specific risk factors, as well as the dose and intensity of the prescribed statin.

One recent study suggests that while the overall chance of developing diabetes is small, when looking at risk by years of exposure, atorvastatin, rosuvastatin, and lovastatin carried the largest risk, whereas the risk was lower with pravastatin and simvastatin.

Risks also seemed lower with fluvastatin and pitavastatin, but there were too few study patients taking those drugs long-term to include in the subanalysis.

With input from the latest guidelines from the American Heart Association and the American Diabetes Association, as well as findings from a clinical guide on statin-associated diabetes, Dr. Hoogwerf suggests in his review that shared decision-making before starting statin therapy of any type include the following considerations/discussion points:

• For all patients: Screening to determine baseline glycemic status; nonstatin therapies to lower cholesterol; and variables associated with an increased risk of diabetes, including antihypertensive drugs.
• For patients without T2D: The possibility of developing T2D, types and doses of statins, and the fact that statin benefits “generally far outweigh” risks of developing diabetes.
• For patients with T2D: Possible small adverse effects on glycemic control; statin benefits in reducing risk for atherosclerotic cardiovascular disease, which “significantly outweigh” the small increase in A1c; and mitigation of adverse glycemic effects of statins with glucose-lowering therapies.

It’s worth noting that the AHA and ADA guidelines, among others, also emphasize that such discussions should include the importance of weight loss, regular exercise, and adhering to a healthy lifestyle to mitigate risks of both diabetes and heart disease, with or without statins.

Dr. Hong, Dr. Nissen, and Dr. Martin report no relevant financial relationships. Dr. Hoogwerf has disclosed ownership interest in Eli Lilly and consulting for MannKind and Zealand Pharmaceuticals.

A version of this article appeared on Medscape.com.

TOPLINE:

Time-restricted eating (TRE), also known as intermittent fasting, for a daily 8-hour period without calorie counting produced greater weight loss among people with type 2 diabetes and obesity, compared with calorie restriction, while hemoglobin A1c levels dropped with both approaches, compared with no intervention.

METHODOLOGY:

• Six-month clinical trial of 75 adult participants with type 2 diabetes and obesity, randomly assigned to either 8-hour TRE (noon to 8 p.m. only) without calorie counting, a 25% daily calorie restriction, or control.

TAKEAWAY:

• The primary outcome, change in body weight at month 6, was –3.56% (P = .004) with TRE vs. –1.78% with calorie restriction (P = .06), compared with controls.
• The mean calorie deficit over the 6 months was –313 kcal/day with TRE, –197 kcal/day with calorie restriction, and –16 kcal/day for controls.
• Self-reported adherence to the regimens was 87% of days with 8-hour TRE vs. 68% reporting adherence with calorie goals over the 6 months.  
• A1c levels were reduced significantly by 0.91% in the TRE group and 0.94% in the calorie-restriction group, relative to controls, with no differences between the two intervention groups.
• No serious adverse events were reported.
• Hypoglycemia and hyperglycemia occurrences didn’t differ between groups.

IN PRACTICE:

“Our findings ... show that TRE is safe in patients who are using either diet alone or medications to control their [type 2 diabetes]. However, for people using sulfonylureas and/or insulin, adopting a TRE regimen will require medication changes and regular monitoring, particularly in the initial stages of the diet.”

SOURCE:

The study was conducted by Vasiliki Pavlou, MS, RD, of the department of kinesiology and nutrition, University of Illinois at Chicago, and colleagues. It was published online in JAMA Network Open.

LIMITATIONS:

• Relatively short trial duration.
• Lack of blinding.
• A higher proportion in the TRE group were using newer type 2 diabetes medications at baseline.
• Self-reported dietary intake.

DISCLOSURES:

The study was supported by the University of Illinois at Chicago, and by grants from the National Institutes of Health. Ms. Pavlou reports no relevant financial relationships. Several authors reported relationships with industry. The full list can be found with the original article.

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

TOPLINE:

Time-restricted eating (TRE), also known as intermittent fasting, for a daily 8-hour period without calorie counting produced greater weight loss among people with type 2 diabetes and obesity, compared with calorie restriction, while hemoglobin A1c levels dropped with both approaches, compared with no intervention.

METHODOLOGY:

• Six-month clinical trial of 75 adult participants with type 2 diabetes and obesity, randomly assigned to either 8-hour TRE (noon to 8 p.m. only) without calorie counting, a 25% daily calorie restriction, or control.

TAKEAWAY:

• The primary outcome, change in body weight at month 6, was –3.56% (P = .004) with TRE vs. –1.78% with calorie restriction (P = .06), compared with controls.
• The mean calorie deficit over the 6 months was –313 kcal/day with TRE, –197 kcal/day with calorie restriction, and –16 kcal/day for controls.
• Self-reported adherence to the regimens was 87% of days with 8-hour TRE vs. 68% reporting adherence with calorie goals over the 6 months.  
• A1c levels were reduced significantly by 0.91% in the TRE group and 0.94% in the calorie-restriction group, relative to controls, with no differences between the two intervention groups.
• No serious adverse events were reported.
• Hypoglycemia and hyperglycemia occurrences didn’t differ between groups.

IN PRACTICE:

“Our findings ... show that TRE is safe in patients who are using either diet alone or medications to control their [type 2 diabetes]. However, for people using sulfonylureas and/or insulin, adopting a TRE regimen will require medication changes and regular monitoring, particularly in the initial stages of the diet.”

SOURCE:

The study was conducted by Vasiliki Pavlou, MS, RD, of the department of kinesiology and nutrition, University of Illinois at Chicago, and colleagues. It was published online in JAMA Network Open.

LIMITATIONS:

• Relatively short trial duration.
• Lack of blinding.
• A higher proportion in the TRE group were using newer type 2 diabetes medications at baseline.
• Self-reported dietary intake.

DISCLOSURES:

The study was supported by the University of Illinois at Chicago, and by grants from the National Institutes of Health. Ms. Pavlou reports no relevant financial relationships. Several authors reported relationships with industry. The full list can be found with the original article.

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

TOPLINE:

Time-restricted eating (TRE), also known as intermittent fasting, for a daily 8-hour period without calorie counting produced greater weight loss among people with type 2 diabetes and obesity, compared with calorie restriction, while hemoglobin A1c levels dropped with both approaches, compared with no intervention.

METHODOLOGY:

• Six-month clinical trial of 75 adult participants with type 2 diabetes and obesity, randomly assigned to either 8-hour TRE (noon to 8 p.m. only) without calorie counting, a 25% daily calorie restriction, or control.

TAKEAWAY:

• The primary outcome, change in body weight at month 6, was –3.56% (P = .004) with TRE vs. –1.78% with calorie restriction (P = .06), compared with controls.
• The mean calorie deficit over the 6 months was –313 kcal/day with TRE, –197 kcal/day with calorie restriction, and –16 kcal/day for controls.
• Self-reported adherence to the regimens was 87% of days with 8-hour TRE vs. 68% reporting adherence with calorie goals over the 6 months.  
• A1c levels were reduced significantly by 0.91% in the TRE group and 0.94% in the calorie-restriction group, relative to controls, with no differences between the two intervention groups.
• No serious adverse events were reported.
• Hypoglycemia and hyperglycemia occurrences didn’t differ between groups.

IN PRACTICE:

“Our findings ... show that TRE is safe in patients who are using either diet alone or medications to control their [type 2 diabetes]. However, for people using sulfonylureas and/or insulin, adopting a TRE regimen will require medication changes and regular monitoring, particularly in the initial stages of the diet.”

SOURCE:

The study was conducted by Vasiliki Pavlou, MS, RD, of the department of kinesiology and nutrition, University of Illinois at Chicago, and colleagues. It was published online in JAMA Network Open.

LIMITATIONS:

• Relatively short trial duration.
• Lack of blinding.
• A higher proportion in the TRE group were using newer type 2 diabetes medications at baseline.
• Self-reported dietary intake.

DISCLOSURES:

The study was supported by the University of Illinois at Chicago, and by grants from the National Institutes of Health. Ms. Pavlou reports no relevant financial relationships. Several authors reported relationships with industry. The full list can be found with the original article.

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

TOPLINE:

The risk for Guillain-Barré syndrome (GBS) is six times higher in people with COVID-19 in the 6 weeks following infection, according to a new study that also showed receipt of the Pfizer-BioNTech mRNA vaccine reduced GSB risk by 59%.

METHODOLOGY:

• The nested-case control study analyzed data from the largest healthcare provider in Israel for 3.2 million patients aged 16 years and older, with no history of GBS.
• GBS cases (n = 76) were identified based on hospital discharge data from January 2021 to June 2022.
• For every GBS case, investigators chose 10 controls at random, matched for age, gender, and follow-up duration (n = 760).
• Investigators examined the association between GBS and SARS-CoV-2 infection, established through documentation of prior positive SARS-CoV-2 test (PCR or antigen), and any COVID-19 vaccine administration.

TAKEAWAY:

• Among those diagnosed with GBS, 8 were exposed to SARS-CoV-2 infection only, 7 were exposed to COVID-19 vaccination only, and 1 patient was exposed to both SARS-CoV-2 infection and COVID-19 vaccination in the prior 6 weeks, leaving 60 GBS patients without exposure to either infection or vaccination.
• All COVID-19 vaccine doses administered in GBS cases within 6 weeks of the index date, and all but two doses administered in controls in the same timeframe, were Pfizer-BioNTech vaccines.
• Compared with people without GBS, those with the condition were more than six times as likely to have had SARS-CoV-2 infection within 6 weeks of GBS diagnosis (adjusted odds ratio, 6.30; 95% confidence interval, 2.55-15.56).
• People who received the COVID-19 vaccine were 59% less likely to develop GBS than those who did not get the vaccine (aOR, 0.41; 95% CI, 0.17-0.96).

IN PRACTICE:

“While Guillain-Barré is extremely rare, people should be aware that having a COVID infection can increase their risk of developing the disorder, and receiving an mRNA vaccine can decrease their risk,” study author Anat Arbel, MD, of Lady Davis Carmel Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel, said in a press release.

SOURCE:

In addition to Dr. Arbel, the other lead author is Haya Bishara, MD, of Lady Davis Carmel Medical Center. The research was published online  in the journal Neurology.

LIMITATIONS:

There is a possibility of misclassification of SARS-CoV-2 infection, which could lead to an overestimation of the magnitude of association between infection and GBS. The diagnosis of GBS relied solely on ICD-9 coding, which has been shown in prior studies to contain errors.

DISCLOSURES:

The study was unfunded. Dr. Bishara and Dr. Arbel report no relevant financial relationships. One co-author, Eitan Auriel, MD, has received lecturer fees from Novo Nordisk, Pfizer, Boehringer Ingelheim, and Medison.

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

TOPLINE:

The risk for Guillain-Barré syndrome (GBS) is six times higher in people with COVID-19 in the 6 weeks following infection, according to a new study that also showed receipt of the Pfizer-BioNTech mRNA vaccine reduced GSB risk by 59%.

METHODOLOGY:

• The nested-case control study analyzed data from the largest healthcare provider in Israel for 3.2 million patients aged 16 years and older, with no history of GBS.
• GBS cases (n = 76) were identified based on hospital discharge data from January 2021 to June 2022.
• For every GBS case, investigators chose 10 controls at random, matched for age, gender, and follow-up duration (n = 760).
• Investigators examined the association between GBS and SARS-CoV-2 infection, established through documentation of prior positive SARS-CoV-2 test (PCR or antigen), and any COVID-19 vaccine administration.

TAKEAWAY:

• Among those diagnosed with GBS, 8 were exposed to SARS-CoV-2 infection only, 7 were exposed to COVID-19 vaccination only, and 1 patient was exposed to both SARS-CoV-2 infection and COVID-19 vaccination in the prior 6 weeks, leaving 60 GBS patients without exposure to either infection or vaccination.
• All COVID-19 vaccine doses administered in GBS cases within 6 weeks of the index date, and all but two doses administered in controls in the same timeframe, were Pfizer-BioNTech vaccines.
• Compared with people without GBS, those with the condition were more than six times as likely to have had SARS-CoV-2 infection within 6 weeks of GBS diagnosis (adjusted odds ratio, 6.30; 95% confidence interval, 2.55-15.56).
• People who received the COVID-19 vaccine were 59% less likely to develop GBS than those who did not get the vaccine (aOR, 0.41; 95% CI, 0.17-0.96).

IN PRACTICE:

“While Guillain-Barré is extremely rare, people should be aware that having a COVID infection can increase their risk of developing the disorder, and receiving an mRNA vaccine can decrease their risk,” study author Anat Arbel, MD, of Lady Davis Carmel Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel, said in a press release.

SOURCE:

In addition to Dr. Arbel, the other lead author is Haya Bishara, MD, of Lady Davis Carmel Medical Center. The research was published online  in the journal Neurology.

LIMITATIONS:

There is a possibility of misclassification of SARS-CoV-2 infection, which could lead to an overestimation of the magnitude of association between infection and GBS. The diagnosis of GBS relied solely on ICD-9 coding, which has been shown in prior studies to contain errors.

DISCLOSURES:

The study was unfunded. Dr. Bishara and Dr. Arbel report no relevant financial relationships. One co-author, Eitan Auriel, MD, has received lecturer fees from Novo Nordisk, Pfizer, Boehringer Ingelheim, and Medison.

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

TOPLINE:

The risk for Guillain-Barré syndrome (GBS) is six times higher in people with COVID-19 in the 6 weeks following infection, according to a new study that also showed receipt of the Pfizer-BioNTech mRNA vaccine reduced GSB risk by 59%.

METHODOLOGY:

• The nested-case control study analyzed data from the largest healthcare provider in Israel for 3.2 million patients aged 16 years and older, with no history of GBS.
• GBS cases (n = 76) were identified based on hospital discharge data from January 2021 to June 2022.
• For every GBS case, investigators chose 10 controls at random, matched for age, gender, and follow-up duration (n = 760).
• Investigators examined the association between GBS and SARS-CoV-2 infection, established through documentation of prior positive SARS-CoV-2 test (PCR or antigen), and any COVID-19 vaccine administration.

TAKEAWAY:

• Among those diagnosed with GBS, 8 were exposed to SARS-CoV-2 infection only, 7 were exposed to COVID-19 vaccination only, and 1 patient was exposed to both SARS-CoV-2 infection and COVID-19 vaccination in the prior 6 weeks, leaving 60 GBS patients without exposure to either infection or vaccination.
• All COVID-19 vaccine doses administered in GBS cases within 6 weeks of the index date, and all but two doses administered in controls in the same timeframe, were Pfizer-BioNTech vaccines.
• Compared with people without GBS, those with the condition were more than six times as likely to have had SARS-CoV-2 infection within 6 weeks of GBS diagnosis (adjusted odds ratio, 6.30; 95% confidence interval, 2.55-15.56).
• People who received the COVID-19 vaccine were 59% less likely to develop GBS than those who did not get the vaccine (aOR, 0.41; 95% CI, 0.17-0.96).

IN PRACTICE:

“While Guillain-Barré is extremely rare, people should be aware that having a COVID infection can increase their risk of developing the disorder, and receiving an mRNA vaccine can decrease their risk,” study author Anat Arbel, MD, of Lady Davis Carmel Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel, said in a press release.

SOURCE:

In addition to Dr. Arbel, the other lead author is Haya Bishara, MD, of Lady Davis Carmel Medical Center. The research was published online  in the journal Neurology.

LIMITATIONS:

There is a possibility of misclassification of SARS-CoV-2 infection, which could lead to an overestimation of the magnitude of association between infection and GBS. The diagnosis of GBS relied solely on ICD-9 coding, which has been shown in prior studies to contain errors.

DISCLOSURES:

The study was unfunded. Dr. Bishara and Dr. Arbel report no relevant financial relationships. One co-author, Eitan Auriel, MD, has received lecturer fees from Novo Nordisk, Pfizer, Boehringer Ingelheim, and Medison.

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

TOPLINE:

Among the 3,188 people with type 2 diabetes who were adherent to their tirzepatide (Mounjaro, Lilly) regimen in four pivotal trials of the agent, a quarter achieved at least a 15% cut from their baseline body weight after 40-42 weeks of treatment, and researchers found seven baseline variables that were significantly linked with a higher incidence of this level of weight loss.

“These findings help inform which people with type 2 diabetes are most likely to achieve greater body weight reduction with improved cardiometabolic risk factors with tirzepatide,” say the authors.

METHODOLOGY:

• Investigators conducted a post hoc analysis of data collected from a total of 3,188 people with type 2 diabetes who had been adherent to their assigned tirzepatide regimen for 40-42 weeks in any one of four pivotal trials of the agent.
• The researchers aimed to identify predictors of a reduction in body weight of at least 15% with tirzepatide treatment at any of the three tested doses – 5 mg, 10 mg, or 15 mg – which were administered by subcutaneous injection once a week.
• All four trials that provided data prohibited concurrent therapy that would promote weight loss, and the people included in the analysis did not receive any rescue medications for controlling glycemia.
• The primary efficacy measure in all four studies was the ability of tirzepatide to improve glycemic control (measured by A1c level), compared with placebo, semaglutide (Ozempic) 1 mg SC once weekly, insulin degludec (Tresiba, Novo Nordisk), or insulin glargine (Basaglar, Lilly).

TAKEAWAY:

• Among the 3,188 people who remained adherent to their tirzepatide regimen for 40-42 weeks, 792 (25%) experienced a weight reduction of at least 15% from baseline.
• Multivariate analysis of baseline covariates showed that these seven factors were significantly linked with greater than or equal to 15% weight loss: higher tirzepatide dose, being female, being of White or Asian race, being of younger age, undergoing treatment with metformin, having better glycemic control (based on lower A1c and lower fasting serum glucose), and having lower non–high-density lipoprotein cholesterol level.
• During follow-up, achievement of at least a 15% cut in baseline body weight was significantly associated with greater reductions in A1c, fasting serum glucose level, waist circumference, blood pressure, serum triglyceride level, and serum level of the liver enzyme alanine transaminase.

IN PRACTICE:

“These findings may provide valuable information to clinicians and people with type 2 diabetes regarding the likelihood of achieving substantial body weight reduction with tirzepatide and also help to signal likely improvements to be seen in a range of cardiometabolic risk parameters with tirzepatide-induced weight loss,” the authors concluded in their report.

SOURCE:

The study was largely run by researchers who are employees of Lilly, the company that markets tirzepatide (Mounjaro). It was published in Diabetes Care.

LIMITATIONS:

• The analysis was post hoc.
• The follow-up was limited.
• The analysis focused entirely on baseline parameters as potential predictors of weight loss magnitude.

DISCLOSURES:

The study was funded by Eli Lilly, the company that markets tirzepatide (Mounjaro) and that sponsored the SURPASS trials. Six authors are employees of Lilly, one is a contractor for Lilly, and the two remaining authors have had financial relationships with Lilly and with several other companies.

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

TOPLINE:

Among the 3,188 people with type 2 diabetes who were adherent to their tirzepatide (Mounjaro, Lilly) regimen in four pivotal trials of the agent, a quarter achieved at least a 15% cut from their baseline body weight after 40-42 weeks of treatment, and researchers found seven baseline variables that were significantly linked with a higher incidence of this level of weight loss.

“These findings help inform which people with type 2 diabetes are most likely to achieve greater body weight reduction with improved cardiometabolic risk factors with tirzepatide,” say the authors.

METHODOLOGY:

• Investigators conducted a post hoc analysis of data collected from a total of 3,188 people with type 2 diabetes who had been adherent to their assigned tirzepatide regimen for 40-42 weeks in any one of four pivotal trials of the agent.
• The researchers aimed to identify predictors of a reduction in body weight of at least 15% with tirzepatide treatment at any of the three tested doses – 5 mg, 10 mg, or 15 mg – which were administered by subcutaneous injection once a week.
• All four trials that provided data prohibited concurrent therapy that would promote weight loss, and the people included in the analysis did not receive any rescue medications for controlling glycemia.
• The primary efficacy measure in all four studies was the ability of tirzepatide to improve glycemic control (measured by A1c level), compared with placebo, semaglutide (Ozempic) 1 mg SC once weekly, insulin degludec (Tresiba, Novo Nordisk), or insulin glargine (Basaglar, Lilly).

TAKEAWAY:

• Among the 3,188 people who remained adherent to their tirzepatide regimen for 40-42 weeks, 792 (25%) experienced a weight reduction of at least 15% from baseline.
• Multivariate analysis of baseline covariates showed that these seven factors were significantly linked with greater than or equal to 15% weight loss: higher tirzepatide dose, being female, being of White or Asian race, being of younger age, undergoing treatment with metformin, having better glycemic control (based on lower A1c and lower fasting serum glucose), and having lower non–high-density lipoprotein cholesterol level.
• During follow-up, achievement of at least a 15% cut in baseline body weight was significantly associated with greater reductions in A1c, fasting serum glucose level, waist circumference, blood pressure, serum triglyceride level, and serum level of the liver enzyme alanine transaminase.

IN PRACTICE:

“These findings may provide valuable information to clinicians and people with type 2 diabetes regarding the likelihood of achieving substantial body weight reduction with tirzepatide and also help to signal likely improvements to be seen in a range of cardiometabolic risk parameters with tirzepatide-induced weight loss,” the authors concluded in their report.

SOURCE:

The study was largely run by researchers who are employees of Lilly, the company that markets tirzepatide (Mounjaro). It was published in Diabetes Care.

LIMITATIONS:

• The analysis was post hoc.
• The follow-up was limited.
• The analysis focused entirely on baseline parameters as potential predictors of weight loss magnitude.

DISCLOSURES:

The study was funded by Eli Lilly, the company that markets tirzepatide (Mounjaro) and that sponsored the SURPASS trials. Six authors are employees of Lilly, one is a contractor for Lilly, and the two remaining authors have had financial relationships with Lilly and with several other companies.

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

TOPLINE:

Among the 3,188 people with type 2 diabetes who were adherent to their tirzepatide (Mounjaro, Lilly) regimen in four pivotal trials of the agent, a quarter achieved at least a 15% cut from their baseline body weight after 40-42 weeks of treatment, and researchers found seven baseline variables that were significantly linked with a higher incidence of this level of weight loss.

“These findings help inform which people with type 2 diabetes are most likely to achieve greater body weight reduction with improved cardiometabolic risk factors with tirzepatide,” say the authors.

METHODOLOGY:

• Investigators conducted a post hoc analysis of data collected from a total of 3,188 people with type 2 diabetes who had been adherent to their assigned tirzepatide regimen for 40-42 weeks in any one of four pivotal trials of the agent.
• The researchers aimed to identify predictors of a reduction in body weight of at least 15% with tirzepatide treatment at any of the three tested doses – 5 mg, 10 mg, or 15 mg – which were administered by subcutaneous injection once a week.
• All four trials that provided data prohibited concurrent therapy that would promote weight loss, and the people included in the analysis did not receive any rescue medications for controlling glycemia.
• The primary efficacy measure in all four studies was the ability of tirzepatide to improve glycemic control (measured by A1c level), compared with placebo, semaglutide (Ozempic) 1 mg SC once weekly, insulin degludec (Tresiba, Novo Nordisk), or insulin glargine (Basaglar, Lilly).

TAKEAWAY:

• Among the 3,188 people who remained adherent to their tirzepatide regimen for 40-42 weeks, 792 (25%) experienced a weight reduction of at least 15% from baseline.
• Multivariate analysis of baseline covariates showed that these seven factors were significantly linked with greater than or equal to 15% weight loss: higher tirzepatide dose, being female, being of White or Asian race, being of younger age, undergoing treatment with metformin, having better glycemic control (based on lower A1c and lower fasting serum glucose), and having lower non–high-density lipoprotein cholesterol level.
• During follow-up, achievement of at least a 15% cut in baseline body weight was significantly associated with greater reductions in A1c, fasting serum glucose level, waist circumference, blood pressure, serum triglyceride level, and serum level of the liver enzyme alanine transaminase.

IN PRACTICE:

“These findings may provide valuable information to clinicians and people with type 2 diabetes regarding the likelihood of achieving substantial body weight reduction with tirzepatide and also help to signal likely improvements to be seen in a range of cardiometabolic risk parameters with tirzepatide-induced weight loss,” the authors concluded in their report.

SOURCE:

The study was largely run by researchers who are employees of Lilly, the company that markets tirzepatide (Mounjaro). It was published in Diabetes Care.

LIMITATIONS:

• The analysis was post hoc.
• The follow-up was limited.
• The analysis focused entirely on baseline parameters as potential predictors of weight loss magnitude.

DISCLOSURES:

The study was funded by Eli Lilly, the company that markets tirzepatide (Mounjaro) and that sponsored the SURPASS trials. Six authors are employees of Lilly, one is a contractor for Lilly, and the two remaining authors have had financial relationships with Lilly and with several other companies.

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