Diabetes

Type 2 diabetes (T2D) is the most common form of diabetes, representing more than 90% of all cases worldwide. The prevalence of T2D is increasing globally, mainly because of behavioral and social factors related to obesity, diet, and physical activity. The International Diabetes Federation estimated in its 2021 report that 537 million adults aged between 20 and 79 years have been diagnosed with diabetes worldwide. The organization predicts an increase to 643 million by 2030 and 743 million by 2045.

The main therapeutic goals for patients with T2D include adequate glycemic control and primary and secondary prevention of atherosclerotic cardiovascular and renal diseases, which represent nearly half of all deaths among adults with T2D. Despite the multiple treatment options available, 16% of adults with T2D have inadequate glycemic control, including hemoglobin A1c levels greater than 9%, even though glycemic control was the focus of the 2017 guidelines of the American College of Physicians.

Therefore, the ACP deemed it necessary to update the previous guidelines, considering new evidence on the efficacy and harms of new pharmacologic treatments in adults with T2D with the goal of reducing the risk for all-cause mortality, cardiovascular morbidity, and progression of chronic kidney disease (CKD) in these patients.
 

New Drugs

The pharmacologic treatments that the ACP considered while updating its guidelines include glucagon-like peptide 1 (GLP-1) receptor agonists (that is, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide), a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide receptor agonist (that is, tirzepatide), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (that is, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), dipeptidyl peptidase 4 (DPP-4) inhibitors (that is, alogliptin, linagliptin, saxagliptin, and sitagliptin), and long-acting insulins (that is, insulin glargine and insulin degludec).

Recommendations

The ACP recommends adding an SGLT-2 inhibitor or a GLP-1 agonist to metformin and lifestyle modifications in adults with inadequately controlled T2D (strong recommendation, high certainty of evidence). Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events (MACE), CKD progression, and hospitalization resulting from heart failure, according to the document. Use a GLP-1 agonist to reduce the risk for all-cause mortality, MACE, and strokes.

SGLT-2 inhibitors and GLP-1 agonists are the only newer pharmacological treatments for T2D that have reduced all-cause mortality than placebo or usual care. In indirect comparison, SGLT-2 inhibitors probably reduce the risk for hospitalization resulting from heart failure, while GLP-1 agonists probably reduce the risk for strokes.

Neither class of drugs causes severe hypoglycemia, but both are associated with various harms, as reported in specific warnings. Both classes of drugs lead to weight loss.

Compared with long-acting insulins, SGLT-2 inhibitors can reduce, and GLP-1 agonists probably reduce, all-cause mortality. Compared with DPP-4 inhibitors, GLP-1 agonists probably reduce all-cause mortality.

Compared with DPP-4 inhibitors, SGLT-2 inhibitors probably reduce MACE, as well as compared with sulfonylureas.

The ACP recommends against adding a DPP-4 inhibitor to metformin and lifestyle modifications in adults with inadequately controlled T2D to reduce morbidity and all-cause mortality (strong recommendation, high certainty of evidence).

Compared with usual therapy, DPP-4 inhibitors do not result in differences in all-cause mortality, MACE, myocardial infarction, stroke, hospitalization for chronic heart failure (CHF), CKD progression, or severe hypoglycemia. Compared with SGLT-2 inhibitors, DPP-4 inhibitors may increase hospitalization caused by CHF and probably increase the risk for MACE and CKD progression. Compared with GLP-1 agonists, they probably increase all-cause mortality and hospitalization caused by CHF and the risk for MACE. Metformin is the most common usual therapy in the studies considered.
 

Considerations for Practice

Metformin (unless contraindicated) and lifestyle modifications represent the first step in managing T2D in most patients, according to the ACP.

The choice of additional therapy requires a risk/benefit assessment and should be personalized on the basis of patient preferences, glycemic control goals, comorbidities, and the risk for hypoglycemia. SGLT-2 inhibitors can be added in patients with T2D and CHF or CKD, according to the ACP. GLP-1 agonists can be added in patients with T2D at increased risk for stroke or for whom total body weight loss is a significant therapeutic goal.

The A1c target should be considered between 7% and 8% in most adults with T2D, and de-escalation of pharmacologic treatments should be considered for A1c levels less than 6.5%. Self-monitoring of blood glucose may not be necessary in patients treated with metformin in combination with an SGLT-2 inhibitor or a GLP-1 agonist, according to the ACP.

The document also holds that, in cases of adequate glycemic control with the addition of an SGLT-2 inhibitor or a GLP-1 agonist, existing treatment with sulfonylureas or long-acting insulin should be reduced or stopped due to the increased risk for severe hypoglycemia.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

Type 2 diabetes (T2D) is the most common form of diabetes, representing more than 90% of all cases worldwide. The prevalence of T2D is increasing globally, mainly because of behavioral and social factors related to obesity, diet, and physical activity. The International Diabetes Federation estimated in its 2021 report that 537 million adults aged between 20 and 79 years have been diagnosed with diabetes worldwide. The organization predicts an increase to 643 million by 2030 and 743 million by 2045.

The main therapeutic goals for patients with T2D include adequate glycemic control and primary and secondary prevention of atherosclerotic cardiovascular and renal diseases, which represent nearly half of all deaths among adults with T2D. Despite the multiple treatment options available, 16% of adults with T2D have inadequate glycemic control, including hemoglobin A1c levels greater than 9%, even though glycemic control was the focus of the 2017 guidelines of the American College of Physicians.

Therefore, the ACP deemed it necessary to update the previous guidelines, considering new evidence on the efficacy and harms of new pharmacologic treatments in adults with T2D with the goal of reducing the risk for all-cause mortality, cardiovascular morbidity, and progression of chronic kidney disease (CKD) in these patients.
 

New Drugs

The pharmacologic treatments that the ACP considered while updating its guidelines include glucagon-like peptide 1 (GLP-1) receptor agonists (that is, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide), a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide receptor agonist (that is, tirzepatide), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (that is, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), dipeptidyl peptidase 4 (DPP-4) inhibitors (that is, alogliptin, linagliptin, saxagliptin, and sitagliptin), and long-acting insulins (that is, insulin glargine and insulin degludec).

Recommendations

The ACP recommends adding an SGLT-2 inhibitor or a GLP-1 agonist to metformin and lifestyle modifications in adults with inadequately controlled T2D (strong recommendation, high certainty of evidence). Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events (MACE), CKD progression, and hospitalization resulting from heart failure, according to the document. Use a GLP-1 agonist to reduce the risk for all-cause mortality, MACE, and strokes.

SGLT-2 inhibitors and GLP-1 agonists are the only newer pharmacological treatments for T2D that have reduced all-cause mortality than placebo or usual care. In indirect comparison, SGLT-2 inhibitors probably reduce the risk for hospitalization resulting from heart failure, while GLP-1 agonists probably reduce the risk for strokes.

Neither class of drugs causes severe hypoglycemia, but both are associated with various harms, as reported in specific warnings. Both classes of drugs lead to weight loss.

Compared with long-acting insulins, SGLT-2 inhibitors can reduce, and GLP-1 agonists probably reduce, all-cause mortality. Compared with DPP-4 inhibitors, GLP-1 agonists probably reduce all-cause mortality.

Compared with DPP-4 inhibitors, SGLT-2 inhibitors probably reduce MACE, as well as compared with sulfonylureas.

The ACP recommends against adding a DPP-4 inhibitor to metformin and lifestyle modifications in adults with inadequately controlled T2D to reduce morbidity and all-cause mortality (strong recommendation, high certainty of evidence).

Compared with usual therapy, DPP-4 inhibitors do not result in differences in all-cause mortality, MACE, myocardial infarction, stroke, hospitalization for chronic heart failure (CHF), CKD progression, or severe hypoglycemia. Compared with SGLT-2 inhibitors, DPP-4 inhibitors may increase hospitalization caused by CHF and probably increase the risk for MACE and CKD progression. Compared with GLP-1 agonists, they probably increase all-cause mortality and hospitalization caused by CHF and the risk for MACE. Metformin is the most common usual therapy in the studies considered.
 

Considerations for Practice

Metformin (unless contraindicated) and lifestyle modifications represent the first step in managing T2D in most patients, according to the ACP.

The choice of additional therapy requires a risk/benefit assessment and should be personalized on the basis of patient preferences, glycemic control goals, comorbidities, and the risk for hypoglycemia. SGLT-2 inhibitors can be added in patients with T2D and CHF or CKD, according to the ACP. GLP-1 agonists can be added in patients with T2D at increased risk for stroke or for whom total body weight loss is a significant therapeutic goal.

The A1c target should be considered between 7% and 8% in most adults with T2D, and de-escalation of pharmacologic treatments should be considered for A1c levels less than 6.5%. Self-monitoring of blood glucose may not be necessary in patients treated with metformin in combination with an SGLT-2 inhibitor or a GLP-1 agonist, according to the ACP.

The document also holds that, in cases of adequate glycemic control with the addition of an SGLT-2 inhibitor or a GLP-1 agonist, existing treatment with sulfonylureas or long-acting insulin should be reduced or stopped due to the increased risk for severe hypoglycemia.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

Type 2 diabetes (T2D) is the most common form of diabetes, representing more than 90% of all cases worldwide. The prevalence of T2D is increasing globally, mainly because of behavioral and social factors related to obesity, diet, and physical activity. The International Diabetes Federation estimated in its 2021 report that 537 million adults aged between 20 and 79 years have been diagnosed with diabetes worldwide. The organization predicts an increase to 643 million by 2030 and 743 million by 2045.

The main therapeutic goals for patients with T2D include adequate glycemic control and primary and secondary prevention of atherosclerotic cardiovascular and renal diseases, which represent nearly half of all deaths among adults with T2D. Despite the multiple treatment options available, 16% of adults with T2D have inadequate glycemic control, including hemoglobin A1c levels greater than 9%, even though glycemic control was the focus of the 2017 guidelines of the American College of Physicians.

Therefore, the ACP deemed it necessary to update the previous guidelines, considering new evidence on the efficacy and harms of new pharmacologic treatments in adults with T2D with the goal of reducing the risk for all-cause mortality, cardiovascular morbidity, and progression of chronic kidney disease (CKD) in these patients.
 

New Drugs

The pharmacologic treatments that the ACP considered while updating its guidelines include glucagon-like peptide 1 (GLP-1) receptor agonists (that is, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide), a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide receptor agonist (that is, tirzepatide), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (that is, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), dipeptidyl peptidase 4 (DPP-4) inhibitors (that is, alogliptin, linagliptin, saxagliptin, and sitagliptin), and long-acting insulins (that is, insulin glargine and insulin degludec).

Recommendations

The ACP recommends adding an SGLT-2 inhibitor or a GLP-1 agonist to metformin and lifestyle modifications in adults with inadequately controlled T2D (strong recommendation, high certainty of evidence). Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events (MACE), CKD progression, and hospitalization resulting from heart failure, according to the document. Use a GLP-1 agonist to reduce the risk for all-cause mortality, MACE, and strokes.

SGLT-2 inhibitors and GLP-1 agonists are the only newer pharmacological treatments for T2D that have reduced all-cause mortality than placebo or usual care. In indirect comparison, SGLT-2 inhibitors probably reduce the risk for hospitalization resulting from heart failure, while GLP-1 agonists probably reduce the risk for strokes.

Neither class of drugs causes severe hypoglycemia, but both are associated with various harms, as reported in specific warnings. Both classes of drugs lead to weight loss.

Compared with long-acting insulins, SGLT-2 inhibitors can reduce, and GLP-1 agonists probably reduce, all-cause mortality. Compared with DPP-4 inhibitors, GLP-1 agonists probably reduce all-cause mortality.

Compared with DPP-4 inhibitors, SGLT-2 inhibitors probably reduce MACE, as well as compared with sulfonylureas.

The ACP recommends against adding a DPP-4 inhibitor to metformin and lifestyle modifications in adults with inadequately controlled T2D to reduce morbidity and all-cause mortality (strong recommendation, high certainty of evidence).

Compared with usual therapy, DPP-4 inhibitors do not result in differences in all-cause mortality, MACE, myocardial infarction, stroke, hospitalization for chronic heart failure (CHF), CKD progression, or severe hypoglycemia. Compared with SGLT-2 inhibitors, DPP-4 inhibitors may increase hospitalization caused by CHF and probably increase the risk for MACE and CKD progression. Compared with GLP-1 agonists, they probably increase all-cause mortality and hospitalization caused by CHF and the risk for MACE. Metformin is the most common usual therapy in the studies considered.
 

Considerations for Practice

Metformin (unless contraindicated) and lifestyle modifications represent the first step in managing T2D in most patients, according to the ACP.

The choice of additional therapy requires a risk/benefit assessment and should be personalized on the basis of patient preferences, glycemic control goals, comorbidities, and the risk for hypoglycemia. SGLT-2 inhibitors can be added in patients with T2D and CHF or CKD, according to the ACP. GLP-1 agonists can be added in patients with T2D at increased risk for stroke or for whom total body weight loss is a significant therapeutic goal.

The A1c target should be considered between 7% and 8% in most adults with T2D, and de-escalation of pharmacologic treatments should be considered for A1c levels less than 6.5%. Self-monitoring of blood glucose may not be necessary in patients treated with metformin in combination with an SGLT-2 inhibitor or a GLP-1 agonist, according to the ACP.

The document also holds that, in cases of adequate glycemic control with the addition of an SGLT-2 inhibitor or a GLP-1 agonist, existing treatment with sulfonylureas or long-acting insulin should be reduced or stopped due to the increased risk for severe hypoglycemia.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

We recently shared a clinical case drawn from a family medicine practice about the effect of adverse childhood experiences (ACEs) on health. The widespread epidemiology and significant health consequences require a focus on the prevention and management of ACEs. 
 

The Centers for Disease Control and Prevention published an important monograph on ACEs in 2019. Although it is evidence based, most of the interventions recommended to reduce ACEs and their sequelae are larger policy and public health efforts that go well beyond the clinician’s office. Important highlights from these recommended strategies to reduce ACEs include:

• Strengthen economic support for families through policies such as the earned income tax credit and child tax credit.
• Establish routine parental work/shift times to optimize cognitive outcomes in children.
• Promote social norms for healthy families through public health campaigns and legislative efforts to reduce corporal punishment of children. Bystander training that targets boys and men has also proven effective in reducing sexual violence.
• Facilitate early in-home visitation for at-risk families as well as high-quality childcare.
• Employ social-emotional learning approaches for children and adolescents, which can improve aggressive or violent behavior, rates of substance use, and academic success.
• Connect youth to after-school programs featuring caring adults.

But clinicians still play a vital role in the prevention and management of ACEs among their patients. Akin to gathering a patient’s past medical history or family history is initiating universal ACE screening in practice and exploring related topics in conversation.

The ACEs Aware initiative in California provides a comprehensive ACE screening clinical workflow to help implement these conversations in practice, including the assessment of associated health conditions and their appropriate clinical follow-up. While it is encouraged to universally screen patients, the key screenings to prioritize for the pediatric population are “parental depression, severe stress, unhealthy drug use, domestic violence, harsh punishment, [and] food insecurity.” Moreover, a systematic review by Steen and colleagues shared insight into newer interpretations of ACE screening which relate trauma to “[...] community violence, poverty, housing instability, structural racism, environmental blight, and climate change.” 

These exposures are now being investigated for a connection to the toxic stress response. In the long term, this genetic regulatory mechanism can be affected by “high doses of cumulative adversity experienced during critical and sensitive periods of early life development — without the buffering protections of trusted, nurturing caregivers and safe, stable environments.” This micro and macro lens fosters a deeper clinician understanding of a patient’s trauma origin and can better guide appropriate clinical follow-up. 

ACE-associated health conditions can be neurologic, endocrine, metabolic, or immune system–related. Early diagnosis and treatment of these conditions can help prevent long-term health care complications, costly for both patient and the health care system. 

After the initial clinical assessment, physicians can educate patients about the ways that ACE-associated health conditions are a consequence of toxic stress exposure. From there, physicians should rely on a broader integrated health team, within the health system and the community, to offer clinical interventions and services to mitigate patients’ toxic stress. The ACEs Aware Stress Buster wheel highlights seven targets to strategize stress regulation. This wheel can be used to identify existing protective factors for patients and track treatment progress, which may buffer the negative impact of stressors and contribute to health and resilience. 

The burden of universal screenings in primary care is high. Without ACE screening, however, the opportunity to address downstream health effects from toxic stress may be lost. Dubowitz and colleagues suggest ways to successfully incorporate ACE screenings in clinical workflow:

• Utilize technology to implement a streamlined referral processing/tracking system.
• Train clinicians to respond competently to positive ACE screens.
• Gather in-network and community-based resources for patients.

In addition, prioritize screening for families with children younger than 6 years of age to begin interventions as early as possible. Primary care clinicians have the unique opportunity to provide appropriate intervention over continual care. An intervention as simple as encouraging pediatric patient involvement in after-school programs may mitigate toxic stress and prevent the development of an ACE-associated health condition. 

Dr. Vega, Health Sciences Clinical Professor, Family Medicine, University of California, Irvine, disclosed ties with McNeil Pharmaceuticals. Alejandra Hurtado, MD candidate, University of California, Irvine School of Medicine, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

We recently shared a clinical case drawn from a family medicine practice about the effect of adverse childhood experiences (ACEs) on health. The widespread epidemiology and significant health consequences require a focus on the prevention and management of ACEs. 
 

The Centers for Disease Control and Prevention published an important monograph on ACEs in 2019. Although it is evidence based, most of the interventions recommended to reduce ACEs and their sequelae are larger policy and public health efforts that go well beyond the clinician’s office. Important highlights from these recommended strategies to reduce ACEs include:

• Strengthen economic support for families through policies such as the earned income tax credit and child tax credit.
• Establish routine parental work/shift times to optimize cognitive outcomes in children.
• Promote social norms for healthy families through public health campaigns and legislative efforts to reduce corporal punishment of children. Bystander training that targets boys and men has also proven effective in reducing sexual violence.
• Facilitate early in-home visitation for at-risk families as well as high-quality childcare.
• Employ social-emotional learning approaches for children and adolescents, which can improve aggressive or violent behavior, rates of substance use, and academic success.
• Connect youth to after-school programs featuring caring adults.

But clinicians still play a vital role in the prevention and management of ACEs among their patients. Akin to gathering a patient’s past medical history or family history is initiating universal ACE screening in practice and exploring related topics in conversation.

The ACEs Aware initiative in California provides a comprehensive ACE screening clinical workflow to help implement these conversations in practice, including the assessment of associated health conditions and their appropriate clinical follow-up. While it is encouraged to universally screen patients, the key screenings to prioritize for the pediatric population are “parental depression, severe stress, unhealthy drug use, domestic violence, harsh punishment, [and] food insecurity.” Moreover, a systematic review by Steen and colleagues shared insight into newer interpretations of ACE screening which relate trauma to “[...] community violence, poverty, housing instability, structural racism, environmental blight, and climate change.” 

These exposures are now being investigated for a connection to the toxic stress response. In the long term, this genetic regulatory mechanism can be affected by “high doses of cumulative adversity experienced during critical and sensitive periods of early life development — without the buffering protections of trusted, nurturing caregivers and safe, stable environments.” This micro and macro lens fosters a deeper clinician understanding of a patient’s trauma origin and can better guide appropriate clinical follow-up. 

ACE-associated health conditions can be neurologic, endocrine, metabolic, or immune system–related. Early diagnosis and treatment of these conditions can help prevent long-term health care complications, costly for both patient and the health care system. 

After the initial clinical assessment, physicians can educate patients about the ways that ACE-associated health conditions are a consequence of toxic stress exposure. From there, physicians should rely on a broader integrated health team, within the health system and the community, to offer clinical interventions and services to mitigate patients’ toxic stress. The ACEs Aware Stress Buster wheel highlights seven targets to strategize stress regulation. This wheel can be used to identify existing protective factors for patients and track treatment progress, which may buffer the negative impact of stressors and contribute to health and resilience. 

The burden of universal screenings in primary care is high. Without ACE screening, however, the opportunity to address downstream health effects from toxic stress may be lost. Dubowitz and colleagues suggest ways to successfully incorporate ACE screenings in clinical workflow:

• Utilize technology to implement a streamlined referral processing/tracking system.
• Train clinicians to respond competently to positive ACE screens.
• Gather in-network and community-based resources for patients.

In addition, prioritize screening for families with children younger than 6 years of age to begin interventions as early as possible. Primary care clinicians have the unique opportunity to provide appropriate intervention over continual care. An intervention as simple as encouraging pediatric patient involvement in after-school programs may mitigate toxic stress and prevent the development of an ACE-associated health condition. 

Dr. Vega, Health Sciences Clinical Professor, Family Medicine, University of California, Irvine, disclosed ties with McNeil Pharmaceuticals. Alejandra Hurtado, MD candidate, University of California, Irvine School of Medicine, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

We recently shared a clinical case drawn from a family medicine practice about the effect of adverse childhood experiences (ACEs) on health. The widespread epidemiology and significant health consequences require a focus on the prevention and management of ACEs. 
 

The Centers for Disease Control and Prevention published an important monograph on ACEs in 2019. Although it is evidence based, most of the interventions recommended to reduce ACEs and their sequelae are larger policy and public health efforts that go well beyond the clinician’s office. Important highlights from these recommended strategies to reduce ACEs include:

• Strengthen economic support for families through policies such as the earned income tax credit and child tax credit.
• Establish routine parental work/shift times to optimize cognitive outcomes in children.
• Promote social norms for healthy families through public health campaigns and legislative efforts to reduce corporal punishment of children. Bystander training that targets boys and men has also proven effective in reducing sexual violence.
• Facilitate early in-home visitation for at-risk families as well as high-quality childcare.
• Employ social-emotional learning approaches for children and adolescents, which can improve aggressive or violent behavior, rates of substance use, and academic success.
• Connect youth to after-school programs featuring caring adults.

But clinicians still play a vital role in the prevention and management of ACEs among their patients. Akin to gathering a patient’s past medical history or family history is initiating universal ACE screening in practice and exploring related topics in conversation.

The ACEs Aware initiative in California provides a comprehensive ACE screening clinical workflow to help implement these conversations in practice, including the assessment of associated health conditions and their appropriate clinical follow-up. While it is encouraged to universally screen patients, the key screenings to prioritize for the pediatric population are “parental depression, severe stress, unhealthy drug use, domestic violence, harsh punishment, [and] food insecurity.” Moreover, a systematic review by Steen and colleagues shared insight into newer interpretations of ACE screening which relate trauma to “[...] community violence, poverty, housing instability, structural racism, environmental blight, and climate change.” 

These exposures are now being investigated for a connection to the toxic stress response. In the long term, this genetic regulatory mechanism can be affected by “high doses of cumulative adversity experienced during critical and sensitive periods of early life development — without the buffering protections of trusted, nurturing caregivers and safe, stable environments.” This micro and macro lens fosters a deeper clinician understanding of a patient’s trauma origin and can better guide appropriate clinical follow-up. 

ACE-associated health conditions can be neurologic, endocrine, metabolic, or immune system–related. Early diagnosis and treatment of these conditions can help prevent long-term health care complications, costly for both patient and the health care system. 

After the initial clinical assessment, physicians can educate patients about the ways that ACE-associated health conditions are a consequence of toxic stress exposure. From there, physicians should rely on a broader integrated health team, within the health system and the community, to offer clinical interventions and services to mitigate patients’ toxic stress. The ACEs Aware Stress Buster wheel highlights seven targets to strategize stress regulation. This wheel can be used to identify existing protective factors for patients and track treatment progress, which may buffer the negative impact of stressors and contribute to health and resilience. 

The burden of universal screenings in primary care is high. Without ACE screening, however, the opportunity to address downstream health effects from toxic stress may be lost. Dubowitz and colleagues suggest ways to successfully incorporate ACE screenings in clinical workflow:

• Utilize technology to implement a streamlined referral processing/tracking system.
• Train clinicians to respond competently to positive ACE screens.
• Gather in-network and community-based resources for patients.

In addition, prioritize screening for families with children younger than 6 years of age to begin interventions as early as possible. Primary care clinicians have the unique opportunity to provide appropriate intervention over continual care. An intervention as simple as encouraging pediatric patient involvement in after-school programs may mitigate toxic stress and prevent the development of an ACE-associated health condition. 

Dr. Vega, Health Sciences Clinical Professor, Family Medicine, University of California, Irvine, disclosed ties with McNeil Pharmaceuticals. Alejandra Hurtado, MD candidate, University of California, Irvine School of Medicine, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Should we now recommend continuous glucose monitoring to all our patients, even those without diabetes? Most of us would instinctively say “no” to this question, but we are seeing opinions from doctors recommending it, and in recent years, scientific literature has focused on the subject. 

Today, anyone can get an arm patch that continuously measures interstitial glucose, which is closely related to blood sugar. The information can be read on a dedicated reader or on a mobile phone by scanning the patch or, with some models, without even doing anything.

There is a consensus for prescribing continuous glucose monitoring for patients with type 1 or type 2 diabetes who are treated with at least three insulin injections. Not only is the use of continuous glucose monitoring much more comfortable than self-monitoring with finger sticks, but continuous monitoring also helps reduce glycosylated hemoglobin while decreasing the risk for hypoglycemia. Recently, another indication has begun to be reimbursed in France: Type 2 diabetes under mono-insulin injection when the diabetes is not well controlled.

But alongside these situations, there are two questions that are worth considering.
 

Untreated Type 2 Diabetes 

First, is continuous glucose monitoring desirable for all patients with diabetes, even those not treated with insulin and even when blood sugar levels are well managed? Intuitively, one might think that it can’t hurt and that continuous monitoring of blood sugar can only improve things. We have some evidence supporting this idea, but the level of proof is quite weak. It is not clear that continuous monitoring can improve patients’ awareness of the impact of dietary choices or physical activity on blood sugar. Obviously, one can imagine that continuously monitoring glucose will encourage a shift toward more beneficial behaviors. But honestly, today, we do not have proof that wearing a continuous glucose monitor can improve behaviors in patients with type 2 diabetes who are treated with noninsulin antidiabetic medications.

Furthermore, a significant study has shown that while the effectiveness is more evident in patients treated with insulin, strong evidence suggests that continuous glucose monitoring could also reduce glycosylated hemoglobin in patients with type 2 diabetes who are not treated with insulin. A close examination of the results suggests that the benefits generally are less than those observed in insulin-treated patients with diabetes.

When we look at the scientific literature, two factors seem particularly important to consider if choosing to prescribe a continuous glucose monitoring sensor. The first is the method used, because the results can vary depending on the method. It appears that only self-monitoring that allows the patient to follow glucose in real time is effective, unlike blind monitoring that allows only a retrospective analysis of blood sugar levels. In the latter case, the patient wears the sensor, and after a week, 10 days, or 15 days, the results are analyzed, possibly with a health care provider. It seems that this is not very effective in improving glycosylated hemoglobin and dietary and physical activity behavior.

The second essential factor to consider is the need for an education program for the use of these sensors to be helpful. If sensors are used but nothing else is done, it does not seem logical. Seeing blood sugar levels without being able to understand them and act accordingly seems of little use. Scientific literature seems to confirm this idea. 
 

Patients Without Diabetes

Now there is another question. We have discussed patients with type 2 diabetes without insulin. It’s trendy to talk about the potential benefits of continuous glucose monitors in patients without diabetes. The idea is emerging that these monitors could be used to refine the diagnosis of diabetes or to better predict the onset of diabetes in the subsequent years.

Others claim that continuous glucose monitors are an effective way to induce a change in dietary and physical activity behaviors in patients with prediabetes. One can, for example, tell a patient, “You are at risk of developing diabetes, so by monitoring your glucose, you will change your behavior.” Honestly, the scientific data we have today do not support these ideas, and I sincerely believe that it is not advisable today to recommend, as some would like, the mass use of monitors, whether in patients with overweight or obesity, or in patients with prediabetes. This goes for suggestions for using the monitor for 7-10 days per year, in the form of a session to try to reduce the risk for diabetes by motivating patients to change their behavior. We have no evidence at all that this can work. And in my opinion, with this kind of discourse, we ultimately risk, as usual, encouraging patients who are already “fans” of self-checks and self-monitoring to get health data, even if they do not know how to interpret it. Maybe even the doctor they ask for interpretation will not be trained to interpret the results of these monitors.

Spreading the idea that monitors are useful for preventing diabetes has a side effect: It hinders progress on the essential issue. Today, one of the problems in diabetes and prediabetes is that screening is not done often enough, and 20% of patients with diabetes are still unaware of their diagnosis. The management of early diabetes or prediabetes, in my opinion, is not optimal in routine care today. So, I think that adding the idea that using monitors could be beneficial dilutes the main information.

Having said that, I sometimes offer continuous glucose monitoring to some of my patients on a case-by-case basis. I believe that with proper support and an educational program, it can be beneficial for certain patients.
 

In Practice

In summary, I am totally opposed to the normalization of the use of monitors. I think it is our role as health care professionals to warn the public that even if it is accessible — anyone can buy a reader, a sensor — it is not necessarily beneficial, and it may even distract us from what is essential. But as a specialist, I think that using a monitor within a genuine care plan seems reasonable. Ultimately, it’s just personalized medicine.

Dr. Hansel is an endocrinologist-diabetologist and nutritionist, Department of Diabetology-Endocrinology-Nutrition, Hôpital Bichat, and a university lecturer and hospital practitioner, Université Paris-Diderot, France. He discloses ties with Iriade, Sanofi-Aventis, and Amgen.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Should we now recommend continuous glucose monitoring to all our patients, even those without diabetes? Most of us would instinctively say “no” to this question, but we are seeing opinions from doctors recommending it, and in recent years, scientific literature has focused on the subject. 

Today, anyone can get an arm patch that continuously measures interstitial glucose, which is closely related to blood sugar. The information can be read on a dedicated reader or on a mobile phone by scanning the patch or, with some models, without even doing anything.

There is a consensus for prescribing continuous glucose monitoring for patients with type 1 or type 2 diabetes who are treated with at least three insulin injections. Not only is the use of continuous glucose monitoring much more comfortable than self-monitoring with finger sticks, but continuous monitoring also helps reduce glycosylated hemoglobin while decreasing the risk for hypoglycemia. Recently, another indication has begun to be reimbursed in France: Type 2 diabetes under mono-insulin injection when the diabetes is not well controlled.

But alongside these situations, there are two questions that are worth considering.
 

Untreated Type 2 Diabetes 

First, is continuous glucose monitoring desirable for all patients with diabetes, even those not treated with insulin and even when blood sugar levels are well managed? Intuitively, one might think that it can’t hurt and that continuous monitoring of blood sugar can only improve things. We have some evidence supporting this idea, but the level of proof is quite weak. It is not clear that continuous monitoring can improve patients’ awareness of the impact of dietary choices or physical activity on blood sugar. Obviously, one can imagine that continuously monitoring glucose will encourage a shift toward more beneficial behaviors. But honestly, today, we do not have proof that wearing a continuous glucose monitor can improve behaviors in patients with type 2 diabetes who are treated with noninsulin antidiabetic medications.

Furthermore, a significant study has shown that while the effectiveness is more evident in patients treated with insulin, strong evidence suggests that continuous glucose monitoring could also reduce glycosylated hemoglobin in patients with type 2 diabetes who are not treated with insulin. A close examination of the results suggests that the benefits generally are less than those observed in insulin-treated patients with diabetes.

When we look at the scientific literature, two factors seem particularly important to consider if choosing to prescribe a continuous glucose monitoring sensor. The first is the method used, because the results can vary depending on the method. It appears that only self-monitoring that allows the patient to follow glucose in real time is effective, unlike blind monitoring that allows only a retrospective analysis of blood sugar levels. In the latter case, the patient wears the sensor, and after a week, 10 days, or 15 days, the results are analyzed, possibly with a health care provider. It seems that this is not very effective in improving glycosylated hemoglobin and dietary and physical activity behavior.

The second essential factor to consider is the need for an education program for the use of these sensors to be helpful. If sensors are used but nothing else is done, it does not seem logical. Seeing blood sugar levels without being able to understand them and act accordingly seems of little use. Scientific literature seems to confirm this idea. 
 

Patients Without Diabetes

Now there is another question. We have discussed patients with type 2 diabetes without insulin. It’s trendy to talk about the potential benefits of continuous glucose monitors in patients without diabetes. The idea is emerging that these monitors could be used to refine the diagnosis of diabetes or to better predict the onset of diabetes in the subsequent years.

Others claim that continuous glucose monitors are an effective way to induce a change in dietary and physical activity behaviors in patients with prediabetes. One can, for example, tell a patient, “You are at risk of developing diabetes, so by monitoring your glucose, you will change your behavior.” Honestly, the scientific data we have today do not support these ideas, and I sincerely believe that it is not advisable today to recommend, as some would like, the mass use of monitors, whether in patients with overweight or obesity, or in patients with prediabetes. This goes for suggestions for using the monitor for 7-10 days per year, in the form of a session to try to reduce the risk for diabetes by motivating patients to change their behavior. We have no evidence at all that this can work. And in my opinion, with this kind of discourse, we ultimately risk, as usual, encouraging patients who are already “fans” of self-checks and self-monitoring to get health data, even if they do not know how to interpret it. Maybe even the doctor they ask for interpretation will not be trained to interpret the results of these monitors.

Spreading the idea that monitors are useful for preventing diabetes has a side effect: It hinders progress on the essential issue. Today, one of the problems in diabetes and prediabetes is that screening is not done often enough, and 20% of patients with diabetes are still unaware of their diagnosis. The management of early diabetes or prediabetes, in my opinion, is not optimal in routine care today. So, I think that adding the idea that using monitors could be beneficial dilutes the main information.

Having said that, I sometimes offer continuous glucose monitoring to some of my patients on a case-by-case basis. I believe that with proper support and an educational program, it can be beneficial for certain patients.
 

In Practice

In summary, I am totally opposed to the normalization of the use of monitors. I think it is our role as health care professionals to warn the public that even if it is accessible — anyone can buy a reader, a sensor — it is not necessarily beneficial, and it may even distract us from what is essential. But as a specialist, I think that using a monitor within a genuine care plan seems reasonable. Ultimately, it’s just personalized medicine.

Dr. Hansel is an endocrinologist-diabetologist and nutritionist, Department of Diabetology-Endocrinology-Nutrition, Hôpital Bichat, and a university lecturer and hospital practitioner, Université Paris-Diderot, France. He discloses ties with Iriade, Sanofi-Aventis, and Amgen.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Should we now recommend continuous glucose monitoring to all our patients, even those without diabetes? Most of us would instinctively say “no” to this question, but we are seeing opinions from doctors recommending it, and in recent years, scientific literature has focused on the subject. 

Today, anyone can get an arm patch that continuously measures interstitial glucose, which is closely related to blood sugar. The information can be read on a dedicated reader or on a mobile phone by scanning the patch or, with some models, without even doing anything.

There is a consensus for prescribing continuous glucose monitoring for patients with type 1 or type 2 diabetes who are treated with at least three insulin injections. Not only is the use of continuous glucose monitoring much more comfortable than self-monitoring with finger sticks, but continuous monitoring also helps reduce glycosylated hemoglobin while decreasing the risk for hypoglycemia. Recently, another indication has begun to be reimbursed in France: Type 2 diabetes under mono-insulin injection when the diabetes is not well controlled.

But alongside these situations, there are two questions that are worth considering.
 

Untreated Type 2 Diabetes 

First, is continuous glucose monitoring desirable for all patients with diabetes, even those not treated with insulin and even when blood sugar levels are well managed? Intuitively, one might think that it can’t hurt and that continuous monitoring of blood sugar can only improve things. We have some evidence supporting this idea, but the level of proof is quite weak. It is not clear that continuous monitoring can improve patients’ awareness of the impact of dietary choices or physical activity on blood sugar. Obviously, one can imagine that continuously monitoring glucose will encourage a shift toward more beneficial behaviors. But honestly, today, we do not have proof that wearing a continuous glucose monitor can improve behaviors in patients with type 2 diabetes who are treated with noninsulin antidiabetic medications.

Furthermore, a significant study has shown that while the effectiveness is more evident in patients treated with insulin, strong evidence suggests that continuous glucose monitoring could also reduce glycosylated hemoglobin in patients with type 2 diabetes who are not treated with insulin. A close examination of the results suggests that the benefits generally are less than those observed in insulin-treated patients with diabetes.

When we look at the scientific literature, two factors seem particularly important to consider if choosing to prescribe a continuous glucose monitoring sensor. The first is the method used, because the results can vary depending on the method. It appears that only self-monitoring that allows the patient to follow glucose in real time is effective, unlike blind monitoring that allows only a retrospective analysis of blood sugar levels. In the latter case, the patient wears the sensor, and after a week, 10 days, or 15 days, the results are analyzed, possibly with a health care provider. It seems that this is not very effective in improving glycosylated hemoglobin and dietary and physical activity behavior.

The second essential factor to consider is the need for an education program for the use of these sensors to be helpful. If sensors are used but nothing else is done, it does not seem logical. Seeing blood sugar levels without being able to understand them and act accordingly seems of little use. Scientific literature seems to confirm this idea. 
 

Patients Without Diabetes

Now there is another question. We have discussed patients with type 2 diabetes without insulin. It’s trendy to talk about the potential benefits of continuous glucose monitors in patients without diabetes. The idea is emerging that these monitors could be used to refine the diagnosis of diabetes or to better predict the onset of diabetes in the subsequent years.

Others claim that continuous glucose monitors are an effective way to induce a change in dietary and physical activity behaviors in patients with prediabetes. One can, for example, tell a patient, “You are at risk of developing diabetes, so by monitoring your glucose, you will change your behavior.” Honestly, the scientific data we have today do not support these ideas, and I sincerely believe that it is not advisable today to recommend, as some would like, the mass use of monitors, whether in patients with overweight or obesity, or in patients with prediabetes. This goes for suggestions for using the monitor for 7-10 days per year, in the form of a session to try to reduce the risk for diabetes by motivating patients to change their behavior. We have no evidence at all that this can work. And in my opinion, with this kind of discourse, we ultimately risk, as usual, encouraging patients who are already “fans” of self-checks and self-monitoring to get health data, even if they do not know how to interpret it. Maybe even the doctor they ask for interpretation will not be trained to interpret the results of these monitors.

Spreading the idea that monitors are useful for preventing diabetes has a side effect: It hinders progress on the essential issue. Today, one of the problems in diabetes and prediabetes is that screening is not done often enough, and 20% of patients with diabetes are still unaware of their diagnosis. The management of early diabetes or prediabetes, in my opinion, is not optimal in routine care today. So, I think that adding the idea that using monitors could be beneficial dilutes the main information.

Having said that, I sometimes offer continuous glucose monitoring to some of my patients on a case-by-case basis. I believe that with proper support and an educational program, it can be beneficial for certain patients.
 

In Practice

In summary, I am totally opposed to the normalization of the use of monitors. I think it is our role as health care professionals to warn the public that even if it is accessible — anyone can buy a reader, a sensor — it is not necessarily beneficial, and it may even distract us from what is essential. But as a specialist, I think that using a monitor within a genuine care plan seems reasonable. Ultimately, it’s just personalized medicine.

Dr. Hansel is an endocrinologist-diabetologist and nutritionist, Department of Diabetology-Endocrinology-Nutrition, Hôpital Bichat, and a university lecturer and hospital practitioner, Université Paris-Diderot, France. He discloses ties with Iriade, Sanofi-Aventis, and Amgen.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Among stroke survivors with diabetes or obesity, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduced secondary stroke risk by up to 16%, according to authors of a recent meta-analysis. With benefits across administration routes, dosing regimens, type 2 diabetes status, and total and nonfatal strokes, the findings could improve GLP-1 RA implementation by stroke specialists in patients with stroke history and concurrent type 2 diabetes or obesity, authors said. The study was published online in the International Journal of Stoke.

Extending Longevity

Agents including GLP-1 RAs that have been found to reduce cardiovascular events among patients with type 2 diabetes and patients who are overweight or obese also reduce risk of recurrent stroke among patients with a history of stroke who are overweight, obese, or have metabolic disease, said American Heart Association (AHA) Chief Clinical Science Officer Mitchell S. V. Elkind, MD, who was not involved with the study but was asked to comment.

“Stroke is a leading cause of mortality and the leading cause of serious long-term disability,” he added, “so medications that help to reduce that risk can play an important role in improving overall health and well-being and hopefully reducing premature mortality.”

Investigators Anastasia Adamou, MD, an internal medicine resident at AHEPA University Hospital in Thessaloniki, Greece, and colleagues searched MEDLINE and Scopus for cardiovascular outcome trials involving adults randomly assigned to GLP-1 RAs or placebo through November 2023, ultimately analyzing 11 randomized controlled trials (RCTs).

Among 60,380 participants in the nine studies that assessed total strokes, 2.5% of the GLP-1 RA group experienced strokes during follow-up, versus 3% in the placebo group (relative risk [RR] 0.85, 95% confidence interval [CI] 0.77-0.93). Regarding secondary outcomes, the GLP-1 RA group showed a significantly lower rate of nonfatal strokes versus patients on placebo (RR 0.87, 95% CI 0.79-0.95). Conversely, investigators observed no significant risk difference among the groups regarding fatal strokes, probably due to the low rate of events — 0.3% and 0.4% for treated and untreated patients, respectively.

Subgroup analyses revealed no interaction between dosing frequency and total, nonfatal, or fatal strokes. The investigators observed no difference in nonfatal strokes among participants by type 2 diabetes status and medication administration route (oral versus subcutaneous).

“The oral administration route could provide the advantage of lower local ecchymoses and allergic reactions due to subcutaneous infusions,” Dr. Adamou said in an interview. But because oral administration demands daily intake, she added, treatment adherence might be affected. “For this reason, our team performed another subgroup analysis to compare the once-a-day to the once-a-month administration. No interaction effect was again presented between the two subgroups. This outcome allows for personalization of the administration method for each patient.”

Addressing Underutilization

Despite more than 2 decades of widespread use and well-established effects on body weight, HbA1c, and cardiovascular risk, GLP-1 RAs remain underutilized, authors wrote. This is especially true in primary care, noted one study published in Clinical Diabetes.

“GLP-1 RAs have been used for many years to treat diabetic patients,” said Dr. Adamou. But because their impact on cardiovascular health regardless of diabetic status is only recently known, she said, physicians are exercising caution when prescribing this medication to patients without diabetes. “This is why more studies need to be available, especially RCTs.”

Most neurologists traditionally have left management of type 2 diabetes and other metabolic disorders to primary care doctors, said Dr. Elkind. “However, these medications are increasingly important to vascular risk reduction and should be considered part of the stroke specialist’s armamentarium.”

Vascular neurologists can play an important role in managing metabolic disease and obesity by recommending GLP-1 RAs for patients with a history of stroke, or by initiating these medications themselves, Dr. Elkind said. “These drugs are likely to become an important part of stroke patients’ medication regimens, along with antithrombotic agents, blood pressure control, and statins. Neurologists are well-positioned to educate other physicians about the important connections among brain, heart, and metabolic health.”

To that end, he said, the AHA will update guidelines for both primary and secondary stroke prevention as warranted by evidence supporting GLP-1 RAs and other medications that could impact stroke risk in type 2 diabetes and related metabolic disorders. However, no guidelines concerning use of GLP-1 RAs for secondary stroke prevention in obesity exist. Here, said Dr. Elkind, the AHA will continue building on its innovative Cardiovascular-Kidney Metabolic Health program, which includes clinical suggestions and may include more formal clinical practice guidelines as the evidence evolves.

Among the main drivers of the initiative, he said, is the recognition that cardiovascular disease — including stroke — is the major cause of death and morbidity among patients with obesity, type 2 diabetes, and metabolic disorders. “Stroke should be considered an important part of overall cardiovascular risk, and the findings that these drugs can help to reduce the risk of stroke specifically is an important additional reason for their use.”

Dr. Elkind and Dr. Adamou reported no conflicting interests. The authors received no financial support for the study.

Among stroke survivors with diabetes or obesity, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduced secondary stroke risk by up to 16%, according to authors of a recent meta-analysis. With benefits across administration routes, dosing regimens, type 2 diabetes status, and total and nonfatal strokes, the findings could improve GLP-1 RA implementation by stroke specialists in patients with stroke history and concurrent type 2 diabetes or obesity, authors said. The study was published online in the International Journal of Stoke.

Extending Longevity

Agents including GLP-1 RAs that have been found to reduce cardiovascular events among patients with type 2 diabetes and patients who are overweight or obese also reduce risk of recurrent stroke among patients with a history of stroke who are overweight, obese, or have metabolic disease, said American Heart Association (AHA) Chief Clinical Science Officer Mitchell S. V. Elkind, MD, who was not involved with the study but was asked to comment.

“Stroke is a leading cause of mortality and the leading cause of serious long-term disability,” he added, “so medications that help to reduce that risk can play an important role in improving overall health and well-being and hopefully reducing premature mortality.”

Investigators Anastasia Adamou, MD, an internal medicine resident at AHEPA University Hospital in Thessaloniki, Greece, and colleagues searched MEDLINE and Scopus for cardiovascular outcome trials involving adults randomly assigned to GLP-1 RAs or placebo through November 2023, ultimately analyzing 11 randomized controlled trials (RCTs).

Among 60,380 participants in the nine studies that assessed total strokes, 2.5% of the GLP-1 RA group experienced strokes during follow-up, versus 3% in the placebo group (relative risk [RR] 0.85, 95% confidence interval [CI] 0.77-0.93). Regarding secondary outcomes, the GLP-1 RA group showed a significantly lower rate of nonfatal strokes versus patients on placebo (RR 0.87, 95% CI 0.79-0.95). Conversely, investigators observed no significant risk difference among the groups regarding fatal strokes, probably due to the low rate of events — 0.3% and 0.4% for treated and untreated patients, respectively.

Subgroup analyses revealed no interaction between dosing frequency and total, nonfatal, or fatal strokes. The investigators observed no difference in nonfatal strokes among participants by type 2 diabetes status and medication administration route (oral versus subcutaneous).

“The oral administration route could provide the advantage of lower local ecchymoses and allergic reactions due to subcutaneous infusions,” Dr. Adamou said in an interview. But because oral administration demands daily intake, she added, treatment adherence might be affected. “For this reason, our team performed another subgroup analysis to compare the once-a-day to the once-a-month administration. No interaction effect was again presented between the two subgroups. This outcome allows for personalization of the administration method for each patient.”

Addressing Underutilization

Despite more than 2 decades of widespread use and well-established effects on body weight, HbA1c, and cardiovascular risk, GLP-1 RAs remain underutilized, authors wrote. This is especially true in primary care, noted one study published in Clinical Diabetes.

“GLP-1 RAs have been used for many years to treat diabetic patients,” said Dr. Adamou. But because their impact on cardiovascular health regardless of diabetic status is only recently known, she said, physicians are exercising caution when prescribing this medication to patients without diabetes. “This is why more studies need to be available, especially RCTs.”

Most neurologists traditionally have left management of type 2 diabetes and other metabolic disorders to primary care doctors, said Dr. Elkind. “However, these medications are increasingly important to vascular risk reduction and should be considered part of the stroke specialist’s armamentarium.”

Vascular neurologists can play an important role in managing metabolic disease and obesity by recommending GLP-1 RAs for patients with a history of stroke, or by initiating these medications themselves, Dr. Elkind said. “These drugs are likely to become an important part of stroke patients’ medication regimens, along with antithrombotic agents, blood pressure control, and statins. Neurologists are well-positioned to educate other physicians about the important connections among brain, heart, and metabolic health.”

To that end, he said, the AHA will update guidelines for both primary and secondary stroke prevention as warranted by evidence supporting GLP-1 RAs and other medications that could impact stroke risk in type 2 diabetes and related metabolic disorders. However, no guidelines concerning use of GLP-1 RAs for secondary stroke prevention in obesity exist. Here, said Dr. Elkind, the AHA will continue building on its innovative Cardiovascular-Kidney Metabolic Health program, which includes clinical suggestions and may include more formal clinical practice guidelines as the evidence evolves.

Among the main drivers of the initiative, he said, is the recognition that cardiovascular disease — including stroke — is the major cause of death and morbidity among patients with obesity, type 2 diabetes, and metabolic disorders. “Stroke should be considered an important part of overall cardiovascular risk, and the findings that these drugs can help to reduce the risk of stroke specifically is an important additional reason for their use.”

Dr. Elkind and Dr. Adamou reported no conflicting interests. The authors received no financial support for the study.

Among stroke survivors with diabetes or obesity, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduced secondary stroke risk by up to 16%, according to authors of a recent meta-analysis. With benefits across administration routes, dosing regimens, type 2 diabetes status, and total and nonfatal strokes, the findings could improve GLP-1 RA implementation by stroke specialists in patients with stroke history and concurrent type 2 diabetes or obesity, authors said. The study was published online in the International Journal of Stoke.

Extending Longevity

Agents including GLP-1 RAs that have been found to reduce cardiovascular events among patients with type 2 diabetes and patients who are overweight or obese also reduce risk of recurrent stroke among patients with a history of stroke who are overweight, obese, or have metabolic disease, said American Heart Association (AHA) Chief Clinical Science Officer Mitchell S. V. Elkind, MD, who was not involved with the study but was asked to comment.

“Stroke is a leading cause of mortality and the leading cause of serious long-term disability,” he added, “so medications that help to reduce that risk can play an important role in improving overall health and well-being and hopefully reducing premature mortality.”

Investigators Anastasia Adamou, MD, an internal medicine resident at AHEPA University Hospital in Thessaloniki, Greece, and colleagues searched MEDLINE and Scopus for cardiovascular outcome trials involving adults randomly assigned to GLP-1 RAs or placebo through November 2023, ultimately analyzing 11 randomized controlled trials (RCTs).

Among 60,380 participants in the nine studies that assessed total strokes, 2.5% of the GLP-1 RA group experienced strokes during follow-up, versus 3% in the placebo group (relative risk [RR] 0.85, 95% confidence interval [CI] 0.77-0.93). Regarding secondary outcomes, the GLP-1 RA group showed a significantly lower rate of nonfatal strokes versus patients on placebo (RR 0.87, 95% CI 0.79-0.95). Conversely, investigators observed no significant risk difference among the groups regarding fatal strokes, probably due to the low rate of events — 0.3% and 0.4% for treated and untreated patients, respectively.

Subgroup analyses revealed no interaction between dosing frequency and total, nonfatal, or fatal strokes. The investigators observed no difference in nonfatal strokes among participants by type 2 diabetes status and medication administration route (oral versus subcutaneous).

“The oral administration route could provide the advantage of lower local ecchymoses and allergic reactions due to subcutaneous infusions,” Dr. Adamou said in an interview. But because oral administration demands daily intake, she added, treatment adherence might be affected. “For this reason, our team performed another subgroup analysis to compare the once-a-day to the once-a-month administration. No interaction effect was again presented between the two subgroups. This outcome allows for personalization of the administration method for each patient.”

Addressing Underutilization

Despite more than 2 decades of widespread use and well-established effects on body weight, HbA1c, and cardiovascular risk, GLP-1 RAs remain underutilized, authors wrote. This is especially true in primary care, noted one study published in Clinical Diabetes.

“GLP-1 RAs have been used for many years to treat diabetic patients,” said Dr. Adamou. But because their impact on cardiovascular health regardless of diabetic status is only recently known, she said, physicians are exercising caution when prescribing this medication to patients without diabetes. “This is why more studies need to be available, especially RCTs.”

Most neurologists traditionally have left management of type 2 diabetes and other metabolic disorders to primary care doctors, said Dr. Elkind. “However, these medications are increasingly important to vascular risk reduction and should be considered part of the stroke specialist’s armamentarium.”

Vascular neurologists can play an important role in managing metabolic disease and obesity by recommending GLP-1 RAs for patients with a history of stroke, or by initiating these medications themselves, Dr. Elkind said. “These drugs are likely to become an important part of stroke patients’ medication regimens, along with antithrombotic agents, blood pressure control, and statins. Neurologists are well-positioned to educate other physicians about the important connections among brain, heart, and metabolic health.”

To that end, he said, the AHA will update guidelines for both primary and secondary stroke prevention as warranted by evidence supporting GLP-1 RAs and other medications that could impact stroke risk in type 2 diabetes and related metabolic disorders. However, no guidelines concerning use of GLP-1 RAs for secondary stroke prevention in obesity exist. Here, said Dr. Elkind, the AHA will continue building on its innovative Cardiovascular-Kidney Metabolic Health program, which includes clinical suggestions and may include more formal clinical practice guidelines as the evidence evolves.

Among the main drivers of the initiative, he said, is the recognition that cardiovascular disease — including stroke — is the major cause of death and morbidity among patients with obesity, type 2 diabetes, and metabolic disorders. “Stroke should be considered an important part of overall cardiovascular risk, and the findings that these drugs can help to reduce the risk of stroke specifically is an important additional reason for their use.”

Dr. Elkind and Dr. Adamou reported no conflicting interests. The authors received no financial support for the study.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

High levels of xylitol, a low-calorie sweetener used in many reduced-sugar foods as well as gum and toothpaste, are linked to an increased risk of heart attacks, strokes, and death, says a new study published in the European Heart Journal.

The research team studied more than 3000 people in the US and Europe over 3 years and found that people with the highest amount of xylitol in their plasma were more likely to have a problem with their heart or blood vessels.

To show the early effects of xylitol, researchers studied platelet activity in volunteers who consumed a xylitol-sweetened drink and a glucose-sweetened drink. The xylitol levels went up by 1000 times in people after the xylitol drink but not after the glucose-sweetened drink.

Xylitol is naturally found in small amounts in fruit and vegetables, and it’s been used more as a sugar substitute over the past decade in processed foods, toothpaste, chewing gum, and other products.

“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combating conditions like obesity or diabetes,” Stanley Hazen, MD, chair of the Department of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute, Cleveland, Ohio, said in a news release.

“It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot-related events.”

A similar link between erythritol, another sugar substance, and problems with the heart and blood vessels was found last year by the same research team, the release said.

In a response to the study, the Calorie Control Council, a trade association representing the low- and reduced-calorie food and beverage industry, said xylitol has been approved for decades by government agencies. The study results may not apply to the general population because some people in the study already had a higher risk of having problems with their heart and blood vessels, it said.

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

High levels of xylitol, a low-calorie sweetener used in many reduced-sugar foods as well as gum and toothpaste, are linked to an increased risk of heart attacks, strokes, and death, says a new study published in the European Heart Journal.

The research team studied more than 3000 people in the US and Europe over 3 years and found that people with the highest amount of xylitol in their plasma were more likely to have a problem with their heart or blood vessels.

To show the early effects of xylitol, researchers studied platelet activity in volunteers who consumed a xylitol-sweetened drink and a glucose-sweetened drink. The xylitol levels went up by 1000 times in people after the xylitol drink but not after the glucose-sweetened drink.

Xylitol is naturally found in small amounts in fruit and vegetables, and it’s been used more as a sugar substitute over the past decade in processed foods, toothpaste, chewing gum, and other products.

“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combating conditions like obesity or diabetes,” Stanley Hazen, MD, chair of the Department of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute, Cleveland, Ohio, said in a news release.

“It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot-related events.”

A similar link between erythritol, another sugar substance, and problems with the heart and blood vessels was found last year by the same research team, the release said.

In a response to the study, the Calorie Control Council, a trade association representing the low- and reduced-calorie food and beverage industry, said xylitol has been approved for decades by government agencies. The study results may not apply to the general population because some people in the study already had a higher risk of having problems with their heart and blood vessels, it said.

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

High levels of xylitol, a low-calorie sweetener used in many reduced-sugar foods as well as gum and toothpaste, are linked to an increased risk of heart attacks, strokes, and death, says a new study published in the European Heart Journal.

The research team studied more than 3000 people in the US and Europe over 3 years and found that people with the highest amount of xylitol in their plasma were more likely to have a problem with their heart or blood vessels.

To show the early effects of xylitol, researchers studied platelet activity in volunteers who consumed a xylitol-sweetened drink and a glucose-sweetened drink. The xylitol levels went up by 1000 times in people after the xylitol drink but not after the glucose-sweetened drink.

Xylitol is naturally found in small amounts in fruit and vegetables, and it’s been used more as a sugar substitute over the past decade in processed foods, toothpaste, chewing gum, and other products.

“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combating conditions like obesity or diabetes,” Stanley Hazen, MD, chair of the Department of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute, Cleveland, Ohio, said in a news release.

“It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot-related events.”

A similar link between erythritol, another sugar substance, and problems with the heart and blood vessels was found last year by the same research team, the release said.

In a response to the study, the Calorie Control Council, a trade association representing the low- and reduced-calorie food and beverage industry, said xylitol has been approved for decades by government agencies. The study results may not apply to the general population because some people in the study already had a higher risk of having problems with their heart and blood vessels, it said.

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

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest. 

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)–secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed. ... Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, associate professor of medicine, endocrinology and molecular medicine, and the endocrine fellowship program director at Medical College of Wisconsin in Milwaukee, told this news organization. 

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

 

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said, “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma ... we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test … [i]f you have autonomous secretion by the adrenal, you don’t suppress as much. ... When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]. ... Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.” 

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules ... I don’t think we’re missing florid Cushing.” 

However, Dr. Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”
 

Is Wisconsin Representative of Cushing Everywhere?

Dr. Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%. 

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded. 

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Dr. Carroll said. 

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So ... that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said. 

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders. 

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Dr. Carroll noted. 

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded. 

Dr. Carroll reported consulting and investigator fees from Corcept Therapeutics. Dr. Wardlaw has no disclosures. 
 

A version of this article appeared on Medscape.com.

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest. 

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)–secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed. ... Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, associate professor of medicine, endocrinology and molecular medicine, and the endocrine fellowship program director at Medical College of Wisconsin in Milwaukee, told this news organization. 

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

 

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said, “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma ... we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test … [i]f you have autonomous secretion by the adrenal, you don’t suppress as much. ... When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]. ... Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.” 

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules ... I don’t think we’re missing florid Cushing.” 

However, Dr. Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”
 

Is Wisconsin Representative of Cushing Everywhere?

Dr. Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%. 

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded. 

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Dr. Carroll said. 

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So ... that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said. 

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders. 

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Dr. Carroll noted. 

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded. 

Dr. Carroll reported consulting and investigator fees from Corcept Therapeutics. Dr. Wardlaw has no disclosures. 
 

A version of this article appeared on Medscape.com.

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest. 

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)–secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed. ... Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, associate professor of medicine, endocrinology and molecular medicine, and the endocrine fellowship program director at Medical College of Wisconsin in Milwaukee, told this news organization. 

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

 

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said, “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma ... we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test … [i]f you have autonomous secretion by the adrenal, you don’t suppress as much. ... When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]. ... Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.” 

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules ... I don’t think we’re missing florid Cushing.” 

However, Dr. Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”
 

Is Wisconsin Representative of Cushing Everywhere?

Dr. Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%. 

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded. 

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Dr. Carroll said. 

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So ... that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said. 

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders. 

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Dr. Carroll noted. 

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded. 

Dr. Carroll reported consulting and investigator fees from Corcept Therapeutics. Dr. Wardlaw has no disclosures. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

Long-term exposure to fine particulate matter is associated with higher fasting blood glucose (FBG) levels and an increased type 2 diabetes risk, significantly contributing to the diabetes-related health burden among women of reproductive age.

METHODOLOGY:

• Exposure to fine particulate matter < 2.5 µm (PM2.5) is a known risk factor for type 2 diabetes, but its effect on women of reproductive age, who undergo hormonal fluctuations during reproductive events, is not well studied.
• Researchers evaluated the association of long-term exposure to PM2.5 with FBG levels and diabetes risk in 20,076,032 eligible women of reproductive age (average age, 27.04 years) across 350 cities in China between 2010 and 2015.
• They assessed PM2.5 exposure at the participants’ residential addresses and calculated average long-term exposure at 1 (lag 1 year), 2 (lag 2 years), and 3 years (lag 3 years) before the survey date, as defined by the World Health Organization (WHO).
• The primary outcomes were FBG levels and diabetes prevalence (FBG, ≥ 7 mmol/L, classified as diabetes; FBG, 6.1-7 mmol/L, classified as prediabetes).
• The study also evaluated the diabetes burden attributed to long-term PM2.5 exposure as per the Chinese National Ambient Air Quality Standards (annual mean PM2.5 exposure limit, > 35 µg/m³) and the WHO air quality guideline (annual mean PM2.5 exposure limit, > 5 µg/m³).

TAKEAWAY:

• The median PM2.5 exposure levels over lag periods of 1, 2, and 3 years were 67, 67, and 66 µg/m³, respectively, exceeding the WHO limit by more than 13-fold.
• Each interquartile range increase in the 3-year average PM2.5 exposure by 27 μg/m³ raised FBG levels by 0.078 mmol/L (P < .05), risk for diabetes by 18% (odds ratio [OR], 1.18; 95% CI, 1.16-1.19), and risk for prediabetes by 5% (OR, 1.05; 95% CI, 1.04-1.05).
• Long-term exposure to PM2.5 > 5 µg/m³ and 35 µg/m³ in the previous 3 years corresponded to an additional 41.7 (95% CI, 39.3-44.0) and 78.6 (95% CI, 74.5-82.6) thousand cases of diabetes nationwide, respectively.
• A higher PM2.5 exposure increased FBG levels and risk for diabetes in women with overweight or obesity vs those without and in those aged ≥ 35 years vs < 35 years (P < .001).

IN PRACTICE:

“These findings carry significant public health implications for formulating effective intervention strategies and environmental policies to better protect women’s health, particularly in countries with relatively high levels of air pollution and a large population with diabetes, such as China,” the authors wrote.

SOURCE:

The study, led by Yang Shen, Key Laboratory of Public Health Safety of the Ministry of Education and National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

An error in the measurement of particulate matter exposure may have been possible as residential address estimates were used as a proxy for actual personal exposure. Questionnaires were used to retrospectively collect information on parameters such as smoking and alcohol consumption, which may have introduced recall bias. Data on potential confounders, such as diet and physical activity, were not included. Distinction between type 1 and type 2 diabetes was not reported owing to data collection–related limitations.

DISCLOSURES:

The study was supported by the National Key Research and Development Program of China, Henan Key Research and Development Program, State Key Laboratory of Resources and Environmental Information System, and Three-Year Public Health Action Plan of Shanghai. The authors declared no conflicts of interest.

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

TOPLINE:

Long-term exposure to fine particulate matter is associated with higher fasting blood glucose (FBG) levels and an increased type 2 diabetes risk, significantly contributing to the diabetes-related health burden among women of reproductive age.

METHODOLOGY:

• Exposure to fine particulate matter < 2.5 µm (PM2.5) is a known risk factor for type 2 diabetes, but its effect on women of reproductive age, who undergo hormonal fluctuations during reproductive events, is not well studied.
• Researchers evaluated the association of long-term exposure to PM2.5 with FBG levels and diabetes risk in 20,076,032 eligible women of reproductive age (average age, 27.04 years) across 350 cities in China between 2010 and 2015.
• They assessed PM2.5 exposure at the participants’ residential addresses and calculated average long-term exposure at 1 (lag 1 year), 2 (lag 2 years), and 3 years (lag 3 years) before the survey date, as defined by the World Health Organization (WHO).
• The primary outcomes were FBG levels and diabetes prevalence (FBG, ≥ 7 mmol/L, classified as diabetes; FBG, 6.1-7 mmol/L, classified as prediabetes).
• The study also evaluated the diabetes burden attributed to long-term PM2.5 exposure as per the Chinese National Ambient Air Quality Standards (annual mean PM2.5 exposure limit, > 35 µg/m³) and the WHO air quality guideline (annual mean PM2.5 exposure limit, > 5 µg/m³).

TAKEAWAY:

• The median PM2.5 exposure levels over lag periods of 1, 2, and 3 years were 67, 67, and 66 µg/m³, respectively, exceeding the WHO limit by more than 13-fold.
• Each interquartile range increase in the 3-year average PM2.5 exposure by 27 μg/m³ raised FBG levels by 0.078 mmol/L (P < .05), risk for diabetes by 18% (odds ratio [OR], 1.18; 95% CI, 1.16-1.19), and risk for prediabetes by 5% (OR, 1.05; 95% CI, 1.04-1.05).
• Long-term exposure to PM2.5 > 5 µg/m³ and 35 µg/m³ in the previous 3 years corresponded to an additional 41.7 (95% CI, 39.3-44.0) and 78.6 (95% CI, 74.5-82.6) thousand cases of diabetes nationwide, respectively.
• A higher PM2.5 exposure increased FBG levels and risk for diabetes in women with overweight or obesity vs those without and in those aged ≥ 35 years vs < 35 years (P < .001).

IN PRACTICE:

“These findings carry significant public health implications for formulating effective intervention strategies and environmental policies to better protect women’s health, particularly in countries with relatively high levels of air pollution and a large population with diabetes, such as China,” the authors wrote.

SOURCE:

The study, led by Yang Shen, Key Laboratory of Public Health Safety of the Ministry of Education and National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

An error in the measurement of particulate matter exposure may have been possible as residential address estimates were used as a proxy for actual personal exposure. Questionnaires were used to retrospectively collect information on parameters such as smoking and alcohol consumption, which may have introduced recall bias. Data on potential confounders, such as diet and physical activity, were not included. Distinction between type 1 and type 2 diabetes was not reported owing to data collection–related limitations.

DISCLOSURES:

The study was supported by the National Key Research and Development Program of China, Henan Key Research and Development Program, State Key Laboratory of Resources and Environmental Information System, and Three-Year Public Health Action Plan of Shanghai. The authors declared no conflicts of interest.

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

TOPLINE:

Long-term exposure to fine particulate matter is associated with higher fasting blood glucose (FBG) levels and an increased type 2 diabetes risk, significantly contributing to the diabetes-related health burden among women of reproductive age.

METHODOLOGY:

• Exposure to fine particulate matter < 2.5 µm (PM2.5) is a known risk factor for type 2 diabetes, but its effect on women of reproductive age, who undergo hormonal fluctuations during reproductive events, is not well studied.
• Researchers evaluated the association of long-term exposure to PM2.5 with FBG levels and diabetes risk in 20,076,032 eligible women of reproductive age (average age, 27.04 years) across 350 cities in China between 2010 and 2015.
• They assessed PM2.5 exposure at the participants’ residential addresses and calculated average long-term exposure at 1 (lag 1 year), 2 (lag 2 years), and 3 years (lag 3 years) before the survey date, as defined by the World Health Organization (WHO).
• The primary outcomes were FBG levels and diabetes prevalence (FBG, ≥ 7 mmol/L, classified as diabetes; FBG, 6.1-7 mmol/L, classified as prediabetes).
• The study also evaluated the diabetes burden attributed to long-term PM2.5 exposure as per the Chinese National Ambient Air Quality Standards (annual mean PM2.5 exposure limit, > 35 µg/m³) and the WHO air quality guideline (annual mean PM2.5 exposure limit, > 5 µg/m³).

TAKEAWAY:

• The median PM2.5 exposure levels over lag periods of 1, 2, and 3 years were 67, 67, and 66 µg/m³, respectively, exceeding the WHO limit by more than 13-fold.
• Each interquartile range increase in the 3-year average PM2.5 exposure by 27 μg/m³ raised FBG levels by 0.078 mmol/L (P < .05), risk for diabetes by 18% (odds ratio [OR], 1.18; 95% CI, 1.16-1.19), and risk for prediabetes by 5% (OR, 1.05; 95% CI, 1.04-1.05).
• Long-term exposure to PM2.5 > 5 µg/m³ and 35 µg/m³ in the previous 3 years corresponded to an additional 41.7 (95% CI, 39.3-44.0) and 78.6 (95% CI, 74.5-82.6) thousand cases of diabetes nationwide, respectively.
• A higher PM2.5 exposure increased FBG levels and risk for diabetes in women with overweight or obesity vs those without and in those aged ≥ 35 years vs < 35 years (P < .001).

IN PRACTICE:

“These findings carry significant public health implications for formulating effective intervention strategies and environmental policies to better protect women’s health, particularly in countries with relatively high levels of air pollution and a large population with diabetes, such as China,” the authors wrote.

SOURCE:

The study, led by Yang Shen, Key Laboratory of Public Health Safety of the Ministry of Education and National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

An error in the measurement of particulate matter exposure may have been possible as residential address estimates were used as a proxy for actual personal exposure. Questionnaires were used to retrospectively collect information on parameters such as smoking and alcohol consumption, which may have introduced recall bias. Data on potential confounders, such as diet and physical activity, were not included. Distinction between type 1 and type 2 diabetes was not reported owing to data collection–related limitations.

DISCLOSURES:

The study was supported by the National Key Research and Development Program of China, Henan Key Research and Development Program, State Key Laboratory of Resources and Environmental Information System, and Three-Year Public Health Action Plan of Shanghai. The authors declared no conflicts of interest.

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

Now that semaglutide (Wegovy), tirzepatide (Zepbound), and other injectables have created an insatiable market for weight loss drugs, biotech and pharmaceutical companies are roaring ahead with oral formulations, which promise a greater level of convenience, in line with patient preference.

One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.

Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD. 

“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”

He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”

Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.

Here’s a look at other promising oral drugs on the horizon.

Oral Semaglutide

The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.

A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.

“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.

Oral Amycretin

Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.

“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”

APH-012

As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity. 

The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.

The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”

Topline data from the first part of the study are expected to be released by the third quarter.

AZD5004

In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.

“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”

Ecnoglutide

In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.

The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.

Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.

The company is also developing an injectable formulation of ecnoglutide.

GSBR-1290

On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June. 

In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.

A global phase 2b obesity study is planned for the fourth quarter of 2024.

Orforglipron

Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027. 

Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks. 

Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.

A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”

VK2735

VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.

In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.

Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
 

A version of this article appeared on Medscape.com.

Now that semaglutide (Wegovy), tirzepatide (Zepbound), and other injectables have created an insatiable market for weight loss drugs, biotech and pharmaceutical companies are roaring ahead with oral formulations, which promise a greater level of convenience, in line with patient preference.

One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.

Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD. 

“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”

He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”

Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.

Here’s a look at other promising oral drugs on the horizon.

Oral Semaglutide

The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.

A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.

“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.

Oral Amycretin

Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.

“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”

APH-012

As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity. 

The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.

The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”

Topline data from the first part of the study are expected to be released by the third quarter.

AZD5004

In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.

“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”

Ecnoglutide

In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.

The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.

Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.

The company is also developing an injectable formulation of ecnoglutide.

GSBR-1290

On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June. 

In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.

A global phase 2b obesity study is planned for the fourth quarter of 2024.

Orforglipron

Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027. 

Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks. 

Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.

A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”

VK2735

VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.

In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.

Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
 

A version of this article appeared on Medscape.com.

Now that semaglutide (Wegovy), tirzepatide (Zepbound), and other injectables have created an insatiable market for weight loss drugs, biotech and pharmaceutical companies are roaring ahead with oral formulations, which promise a greater level of convenience, in line with patient preference.

One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.

Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD. 

“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”

He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”

Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.

Here’s a look at other promising oral drugs on the horizon.

Oral Semaglutide

The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.

A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.

“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.

Oral Amycretin

Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.

“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”

APH-012

As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity. 

The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.

The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”

Topline data from the first part of the study are expected to be released by the third quarter.

AZD5004

In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.

“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”

Ecnoglutide

In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.

The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.

Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.

The company is also developing an injectable formulation of ecnoglutide.

GSBR-1290

On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June. 

In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.

A global phase 2b obesity study is planned for the fourth quarter of 2024.

Orforglipron

Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027. 

Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks. 

Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.

A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”

VK2735

VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.

In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.

Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
 

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report in the British Medical Journal on the regular use of omega-3 fish oil supplements and the course of cardiovascular disease (CVD).

This is an observational study from the large-scale UK Biobank. The authors divided the participants into those with and those without CVD. In participants without CVD at baseline, those using fish oil supplements regularly had an increased incidence of both atrial fibrillation (AF) and stroke, whereas those with prevalent CVD had a reduction in the progression to major adverse cardiovascular events, which offset any increase in the risk for AF.

Observational studies of omega-3 supplements have potential limitations and confounding, and correlation in these studies does not prove causation. What do the randomized clinical trials of omega-3 supplements show? At least seven randomized trials have looked at AF. A meta-analysis published in Circulation in 2021 showed a dose-response relationship. In trials testing > 1 g/d of marine omega-3 fatty acids, there was close to a 50% overall increase in risk for AF. In studies testing lower doses, there was a very modest 12% increase and a significant dose-response gradient.

For the relationship between omega-3 supplements and major cardiovascular events, at least 15 individual randomized trials have been conducted. There actually have been more meta-analyses of these randomized trials than individual trials. The meta-analyses tend to show a significant reduction of coronary events with omega-3 supplementation, but no reduction in stroke. This is true in both primary and secondary prevention trials.

The one exception to this finding is the REDUCE-IT trial testing high-dose eicosapentaenoic acid (EPA) (4 g/day of icosapent ethyl), and there was a 25%-30% reduction in both cardiovascular events and stroke. But there has been some criticism of the mineral oil placebo used in the REDUCE-IT trial that it may have had adverse effects on biomarkers and might have interfered with the absorption of statins in the placebo group. So, it will be important to have a replication trial of the high-dose EPA, findings in a trial using an inert placebo such as corn oil.

What should be done in the meantime? It’s important to think about prescription omega-3s vs over-the-counter fish oil. The US Food and Drug Administration (FDA) has approved prescription omega-3 medications for several indications, including severely elevated triglyceride levels (> 500 mg/dL). In the REDUCE-IT trial, those who had moderate elevations of triglycerides (≥ 150 mg/dL) or prevalent CVD or diabetes, plus two additional risk factors, were also considered to have indications based on the FDA labeling for icosapent ethyl.

What about patients who don’t meet these criteria for prescription omega-3s? In the VITAL trial (the large-scale primary prevention trial), there was a similar reduction in coronary events but no effect on stroke. Those who seemed to benefit the most in terms of at least 40% reduction in coronary events were participants who had low fish consumption at baseline, had two or more risk factors for cardiovascular disease, or were African American. 

Someone who rarely or never eats fish and has multiple risk factors for CVD, but doesn’t meet criteria for prescription omega-3 medication, may want to discuss with their clinician the use of over-the-counter fish oil supplements. But fish oil and other dietary supplements will never be a substitute for healthy diet and healthy lifestyle. There is a national recommendation for one to two servings of fish per week. For those planning to take fish oil, it’s important to use reputable sources of the supplement, and check the bottle for a quality control seal. It’s also really important to avoid megadoses of fish oil, because high doses have been linked to an increased risk for AF and bleeding.

Dr. Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston, disclosed ties with Mars Symbioscience for the COSMOS trial.

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report in the British Medical Journal on the regular use of omega-3 fish oil supplements and the course of cardiovascular disease (CVD).

This is an observational study from the large-scale UK Biobank. The authors divided the participants into those with and those without CVD. In participants without CVD at baseline, those using fish oil supplements regularly had an increased incidence of both atrial fibrillation (AF) and stroke, whereas those with prevalent CVD had a reduction in the progression to major adverse cardiovascular events, which offset any increase in the risk for AF.

Observational studies of omega-3 supplements have potential limitations and confounding, and correlation in these studies does not prove causation. What do the randomized clinical trials of omega-3 supplements show? At least seven randomized trials have looked at AF. A meta-analysis published in Circulation in 2021 showed a dose-response relationship. In trials testing > 1 g/d of marine omega-3 fatty acids, there was close to a 50% overall increase in risk for AF. In studies testing lower doses, there was a very modest 12% increase and a significant dose-response gradient.

For the relationship between omega-3 supplements and major cardiovascular events, at least 15 individual randomized trials have been conducted. There actually have been more meta-analyses of these randomized trials than individual trials. The meta-analyses tend to show a significant reduction of coronary events with omega-3 supplementation, but no reduction in stroke. This is true in both primary and secondary prevention trials.

The one exception to this finding is the REDUCE-IT trial testing high-dose eicosapentaenoic acid (EPA) (4 g/day of icosapent ethyl), and there was a 25%-30% reduction in both cardiovascular events and stroke. But there has been some criticism of the mineral oil placebo used in the REDUCE-IT trial that it may have had adverse effects on biomarkers and might have interfered with the absorption of statins in the placebo group. So, it will be important to have a replication trial of the high-dose EPA, findings in a trial using an inert placebo such as corn oil.

What should be done in the meantime? It’s important to think about prescription omega-3s vs over-the-counter fish oil. The US Food and Drug Administration (FDA) has approved prescription omega-3 medications for several indications, including severely elevated triglyceride levels (> 500 mg/dL). In the REDUCE-IT trial, those who had moderate elevations of triglycerides (≥ 150 mg/dL) or prevalent CVD or diabetes, plus two additional risk factors, were also considered to have indications based on the FDA labeling for icosapent ethyl.

What about patients who don’t meet these criteria for prescription omega-3s? In the VITAL trial (the large-scale primary prevention trial), there was a similar reduction in coronary events but no effect on stroke. Those who seemed to benefit the most in terms of at least 40% reduction in coronary events were participants who had low fish consumption at baseline, had two or more risk factors for cardiovascular disease, or were African American. 

Someone who rarely or never eats fish and has multiple risk factors for CVD, but doesn’t meet criteria for prescription omega-3 medication, may want to discuss with their clinician the use of over-the-counter fish oil supplements. But fish oil and other dietary supplements will never be a substitute for healthy diet and healthy lifestyle. There is a national recommendation for one to two servings of fish per week. For those planning to take fish oil, it’s important to use reputable sources of the supplement, and check the bottle for a quality control seal. It’s also really important to avoid megadoses of fish oil, because high doses have been linked to an increased risk for AF and bleeding.

Dr. Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston, disclosed ties with Mars Symbioscience for the COSMOS trial.

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report in the British Medical Journal on the regular use of omega-3 fish oil supplements and the course of cardiovascular disease (CVD).

This is an observational study from the large-scale UK Biobank. The authors divided the participants into those with and those without CVD. In participants without CVD at baseline, those using fish oil supplements regularly had an increased incidence of both atrial fibrillation (AF) and stroke, whereas those with prevalent CVD had a reduction in the progression to major adverse cardiovascular events, which offset any increase in the risk for AF.

Observational studies of omega-3 supplements have potential limitations and confounding, and correlation in these studies does not prove causation. What do the randomized clinical trials of omega-3 supplements show? At least seven randomized trials have looked at AF. A meta-analysis published in Circulation in 2021 showed a dose-response relationship. In trials testing > 1 g/d of marine omega-3 fatty acids, there was close to a 50% overall increase in risk for AF. In studies testing lower doses, there was a very modest 12% increase and a significant dose-response gradient.

For the relationship between omega-3 supplements and major cardiovascular events, at least 15 individual randomized trials have been conducted. There actually have been more meta-analyses of these randomized trials than individual trials. The meta-analyses tend to show a significant reduction of coronary events with omega-3 supplementation, but no reduction in stroke. This is true in both primary and secondary prevention trials.

The one exception to this finding is the REDUCE-IT trial testing high-dose eicosapentaenoic acid (EPA) (4 g/day of icosapent ethyl), and there was a 25%-30% reduction in both cardiovascular events and stroke. But there has been some criticism of the mineral oil placebo used in the REDUCE-IT trial that it may have had adverse effects on biomarkers and might have interfered with the absorption of statins in the placebo group. So, it will be important to have a replication trial of the high-dose EPA, findings in a trial using an inert placebo such as corn oil.

What should be done in the meantime? It’s important to think about prescription omega-3s vs over-the-counter fish oil. The US Food and Drug Administration (FDA) has approved prescription omega-3 medications for several indications, including severely elevated triglyceride levels (> 500 mg/dL). In the REDUCE-IT trial, those who had moderate elevations of triglycerides (≥ 150 mg/dL) or prevalent CVD or diabetes, plus two additional risk factors, were also considered to have indications based on the FDA labeling for icosapent ethyl.

What about patients who don’t meet these criteria for prescription omega-3s? In the VITAL trial (the large-scale primary prevention trial), there was a similar reduction in coronary events but no effect on stroke. Those who seemed to benefit the most in terms of at least 40% reduction in coronary events were participants who had low fish consumption at baseline, had two or more risk factors for cardiovascular disease, or were African American. 

Someone who rarely or never eats fish and has multiple risk factors for CVD, but doesn’t meet criteria for prescription omega-3 medication, may want to discuss with their clinician the use of over-the-counter fish oil supplements. But fish oil and other dietary supplements will never be a substitute for healthy diet and healthy lifestyle. There is a national recommendation for one to two servings of fish per week. For those planning to take fish oil, it’s important to use reputable sources of the supplement, and check the bottle for a quality control seal. It’s also really important to avoid megadoses of fish oil, because high doses have been linked to an increased risk for AF and bleeding.

Dr. Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston, disclosed ties with Mars Symbioscience for the COSMOS trial.

A version of this article appeared on Medscape.com.