An important new initiative to reclassify psychiatric medications is underway. Currently, psychotropic drugs are named primarily for their clinical use, usually as a member of 1 of 6 classes: antipsychotic, anti‑depressant, mood stabilizer, stimulant, anxiolytic, and hypnotic.^1,2

This naming system creates confusion because so-called antidepressants commonly are used as anxiolytics, antipsychotics increasingly are used as antidepressants, and so on.^1,2

Vocabulary based on clinical indications also leads to difficulty in classifying new agents, especially those with novel mechanisms of action or clinical uses. Therefore, there is a need to make the names of psychotropic drugs more rational and scientifically based, rather than indication-based. A task force of experts from major psychopharmacology societies around the world is developing an alternative naming system that is increasingly being accepted by the major experts and journals throughout the world, called Neuroscience-based Nomenclature (NbN).^3-5

So, what is NbN?

First and foremost, NbN renames the >100 known psychotropic drugs by 1 of the 11 principle pharmacological domains that include well-known terms such as serotonin dopamine, acetylcholine, and GABA (Table 1). Also included in NbN are 9 familiar modes of action, such as agonist, antagonist, reuptake inhibitor, and enzyme inhibitors (Table 2).^3-5

NbN has 4 additional dimensions or layers^3-5:

• The first layer enumerates the official indications as recognized by the regulatory agencies (ie, the FDA and other government organizations).
• The second layer states efficacy based on randomized controlled trials or substantial, evidence-based clinical data, as well as side effects (not the exhaustive list provided in manufacturers’ package inserts, but only the most common ones).
• The third layer is comprised of practical notes, highlighting potentially important drug interactions, metabolic issues, and specific warnings.
• The fourth section summarizes the neurobiological effects in laboratory animals and humans.

Specific dosages and titration regimens are not provided because they can vary among different countries, and NbN is intended for nomenclature and classification, not as a prescribing guide.

How does it work in practice?

Major journals in the field have begun adapting NbN for their published papers and Current Psychiatry is joining them. Specifically, journals adapting NbN will require authors to clarify the meaning of terms they use for drugs by defining as “antipsychotic,” for example, along with the NbN term (eg, dopamine D2 antagonist) where the drug name first appears in the paper. To make all new papers searchable by NbN terminology, the NbN of the drugs that the paper covers should be added to the keywords of the paper. The new keywords will include those relevant 11 pharmacological domains and 9 modes of action of the drugs discussed in the paper, which will make the process easier for authors and readers searching for drugs in our publications. To “translate” between old and new nomenclature, the easiest and recommended way is to use the free NbN app, which is available on the project’s Web site (http://nbnomenclature.org), as well as Google Play and iTunes. We recommend that journal editors include in their author instructions a link to the glossary that illustrates NbN in practice (http://nbnomenclature.org/authors).

What is the current status?

Two international organizations endorse NbN, and the chief editors of nearly 3 dozen scientific journals, including Current Psychiatry, support the development of this classification system for eventual implementation within the scientific literature. Presentations at symposia at international meetings also have taken place or are ongoing, including a scientific session at the 2016 American Psychiatric Association (APA) annual meeting and another planned for the Presidential Symposium at 2017 APA annual meeting; other presentations are scheduled at the American College of Neuropsychopharmacology in December 2017 and the European College of Neuropsychopharmacology in September 2017.

Clinicians should start adopting the NbN for the psychotropic drugs they prescribe every day. It is more scientific and consistent with the mechanism of action than with a specific disorder because many psychotropic medications have been found to be useful in >1 psychiatric disorder.

An important new initiative to reclassify psychiatric medications is underway. Currently, psychotropic drugs are named primarily for their clinical use, usually as a member of 1 of 6 classes: antipsychotic, anti‑depressant, mood stabilizer, stimulant, anxiolytic, and hypnotic.^1,2

This naming system creates confusion because so-called antidepressants commonly are used as anxiolytics, antipsychotics increasingly are used as antidepressants, and so on.^1,2

Vocabulary based on clinical indications also leads to difficulty in classifying new agents, especially those with novel mechanisms of action or clinical uses. Therefore, there is a need to make the names of psychotropic drugs more rational and scientifically based, rather than indication-based. A task force of experts from major psychopharmacology societies around the world is developing an alternative naming system that is increasingly being accepted by the major experts and journals throughout the world, called Neuroscience-based Nomenclature (NbN).^3-5

So, what is NbN?

First and foremost, NbN renames the >100 known psychotropic drugs by 1 of the 11 principle pharmacological domains that include well-known terms such as serotonin dopamine, acetylcholine, and GABA (Table 1). Also included in NbN are 9 familiar modes of action, such as agonist, antagonist, reuptake inhibitor, and enzyme inhibitors (Table 2).^3-5

NbN has 4 additional dimensions or layers^3-5:

• The first layer enumerates the official indications as recognized by the regulatory agencies (ie, the FDA and other government organizations).
• The second layer states efficacy based on randomized controlled trials or substantial, evidence-based clinical data, as well as side effects (not the exhaustive list provided in manufacturers’ package inserts, but only the most common ones).
• The third layer is comprised of practical notes, highlighting potentially important drug interactions, metabolic issues, and specific warnings.
• The fourth section summarizes the neurobiological effects in laboratory animals and humans.

Specific dosages and titration regimens are not provided because they can vary among different countries, and NbN is intended for nomenclature and classification, not as a prescribing guide.

How does it work in practice?

Major journals in the field have begun adapting NbN for their published papers and Current Psychiatry is joining them. Specifically, journals adapting NbN will require authors to clarify the meaning of terms they use for drugs by defining as “antipsychotic,” for example, along with the NbN term (eg, dopamine D2 antagonist) where the drug name first appears in the paper. To make all new papers searchable by NbN terminology, the NbN of the drugs that the paper covers should be added to the keywords of the paper. The new keywords will include those relevant 11 pharmacological domains and 9 modes of action of the drugs discussed in the paper, which will make the process easier for authors and readers searching for drugs in our publications. To “translate” between old and new nomenclature, the easiest and recommended way is to use the free NbN app, which is available on the project’s Web site (http://nbnomenclature.org), as well as Google Play and iTunes. We recommend that journal editors include in their author instructions a link to the glossary that illustrates NbN in practice (http://nbnomenclature.org/authors).

What is the current status?

Two international organizations endorse NbN, and the chief editors of nearly 3 dozen scientific journals, including Current Psychiatry, support the development of this classification system for eventual implementation within the scientific literature. Presentations at symposia at international meetings also have taken place or are ongoing, including a scientific session at the 2016 American Psychiatric Association (APA) annual meeting and another planned for the Presidential Symposium at 2017 APA annual meeting; other presentations are scheduled at the American College of Neuropsychopharmacology in December 2017 and the European College of Neuropsychopharmacology in September 2017.

Clinicians should start adopting the NbN for the psychotropic drugs they prescribe every day. It is more scientific and consistent with the mechanism of action than with a specific disorder because many psychotropic medications have been found to be useful in >1 psychiatric disorder.

An important new initiative to reclassify psychiatric medications is underway. Currently, psychotropic drugs are named primarily for their clinical use, usually as a member of 1 of 6 classes: antipsychotic, anti‑depressant, mood stabilizer, stimulant, anxiolytic, and hypnotic.^1,2

This naming system creates confusion because so-called antidepressants commonly are used as anxiolytics, antipsychotics increasingly are used as antidepressants, and so on.^1,2

Vocabulary based on clinical indications also leads to difficulty in classifying new agents, especially those with novel mechanisms of action or clinical uses. Therefore, there is a need to make the names of psychotropic drugs more rational and scientifically based, rather than indication-based. A task force of experts from major psychopharmacology societies around the world is developing an alternative naming system that is increasingly being accepted by the major experts and journals throughout the world, called Neuroscience-based Nomenclature (NbN).^3-5

So, what is NbN?

First and foremost, NbN renames the >100 known psychotropic drugs by 1 of the 11 principle pharmacological domains that include well-known terms such as serotonin dopamine, acetylcholine, and GABA (Table 1). Also included in NbN are 9 familiar modes of action, such as agonist, antagonist, reuptake inhibitor, and enzyme inhibitors (Table 2).^3-5

NbN has 4 additional dimensions or layers^3-5:

• The first layer enumerates the official indications as recognized by the regulatory agencies (ie, the FDA and other government organizations).
• The second layer states efficacy based on randomized controlled trials or substantial, evidence-based clinical data, as well as side effects (not the exhaustive list provided in manufacturers’ package inserts, but only the most common ones).
• The third layer is comprised of practical notes, highlighting potentially important drug interactions, metabolic issues, and specific warnings.
• The fourth section summarizes the neurobiological effects in laboratory animals and humans.

Specific dosages and titration regimens are not provided because they can vary among different countries, and NbN is intended for nomenclature and classification, not as a prescribing guide.

How does it work in practice?

Major journals in the field have begun adapting NbN for their published papers and Current Psychiatry is joining them. Specifically, journals adapting NbN will require authors to clarify the meaning of terms they use for drugs by defining as “antipsychotic,” for example, along with the NbN term (eg, dopamine D2 antagonist) where the drug name first appears in the paper. To make all new papers searchable by NbN terminology, the NbN of the drugs that the paper covers should be added to the keywords of the paper. The new keywords will include those relevant 11 pharmacological domains and 9 modes of action of the drugs discussed in the paper, which will make the process easier for authors and readers searching for drugs in our publications. To “translate” between old and new nomenclature, the easiest and recommended way is to use the free NbN app, which is available on the project’s Web site (http://nbnomenclature.org), as well as Google Play and iTunes. We recommend that journal editors include in their author instructions a link to the glossary that illustrates NbN in practice (http://nbnomenclature.org/authors).

What is the current status?

Two international organizations endorse NbN, and the chief editors of nearly 3 dozen scientific journals, including Current Psychiatry, support the development of this classification system for eventual implementation within the scientific literature. Presentations at symposia at international meetings also have taken place or are ongoing, including a scientific session at the 2016 American Psychiatric Association (APA) annual meeting and another planned for the Presidential Symposium at 2017 APA annual meeting; other presentations are scheduled at the American College of Neuropsychopharmacology in December 2017 and the European College of Neuropsychopharmacology in September 2017.

Clinicians should start adopting the NbN for the psychotropic drugs they prescribe every day. It is more scientific and consistent with the mechanism of action than with a specific disorder because many psychotropic medications have been found to be useful in >1 psychiatric disorder.

CASE Unresponsive and suicidal

Mr. Z, age 25, an unemployed immigrant from Eastern Europe, is found unresponsive at a subway station. Workup in the emergency room reveals a positive urine toxicology for benzodiazepines and a blood alcohol level of 101.6 mg/dL. When Mr. Z regains consciousness the next day, he says that he is suicidal. He recently broke up with his girlfriend and feels worthless, hopeless, and depressed. As a suicide attempt, he took quetiapine and diazepam chased with vodka.

Mr. Z reports a history of suicide attempts. He says he has been suffering from depression most of his life and has been diagnosed with bipolar I disorder and borderline personality disorder. His medication regimen consists of quetiapine, 200 mg/d, and duloxetine, 20 mg/d.

Before immigrating to the United States 5 years ago, he attempted to overdose on his mother’s prescribed diazepam and was in a coma for 2 days. Recently, he stole a bicycle with the intent of provoking the police to kill him. When caught, he deliberately disobeyed the officer’s order and advanced toward the officer in an aggressive manner. However, the officer stopped Mr. Z using a stun gun. Mr. Z reports that he still feels angry that his suicide attempt failed. He is an Orthodox Christian and says he is “very religious.”

[polldaddy:9731423]

The authors’ observations

The means of suicide differ among individuals. Some attempt suicide by themselves; others through the involuntary participation of others, such as the police. This is known as SBC. Other terms include “suicide by means of victim-precipitated homicide,”¹ “hetero-suicide,”² “suicide by proxy,”³ “copicide,”⁴ and “law enforcement-forced-assisted suicide.”^5,6 SBC accounts for 10%⁷ to 36%⁶ of police shootings and can cause serious stress for the officers involved and creates a strain between the police and the community.⁸

SBC was first mentioned as “suicide by means of victim-precipitated homicide.” Wolfgang⁵ reported 588 cases of police officer-involved shooting in Philadelphia between January 1948 and December 31, 1952, and, concluded that 150 of these cases (26%) fit criteria for what the author termed “victim-precipitated homicide” because the victims involved were the direct precipitants of the situation leading to their death. Wolfgang stated:

Instead of a murderer performing the act of suicide by killing another person who represents the murder’s unconscious, and instead of a suicide representing the desire to kill turned on [the] self, the victim in these victim-precipitated homicide cases is considered to be a suicide prone [individual] who manifests his desire to destroy [him]self by engaging another person to perform the act.

The term “SBC” was coined in 1983 by Karl Harris, a Los Angeles County medical examiner.⁸ The social repercussions of this modality attracts media attention because of its negative social consequences.

Characteristics of SBC

SBC has characteristics similar to other means of suicide; it is more prevalent among men with psychiatric disorders, including major depression, bipolar disorders, schizophrenia, substance use disorders,⁹ poor stress response skills, recent stressors, and adverse life events,¹⁰ and history of suicide attempts.

Psychosocial characteristics include:

• mean age 31.8 years¹
• male sex (98%)
• white (52%)
• approximately 40% involve some form of relationship conflict.⁶

In psychological autopsy studies, an estimated 70.5% of those involved in a SBC incident had ≥1 stressful life events,¹ including terminal illness, loss of a job, a lawsuit, or domestic issues. However, the reason is unknown for the remaining 28% cases.² Thirty-five percent of those involved in SBC incidents were married, 13.5% divorced, and 46.7% single.¹ Seventy-seven percent had low socioeconomic status,¹¹ with 49.3% unemployed at the time of the SBC incident.¹

Pathological characteristics of SBC and other suicide means are similar. Among SBC cases, 39% had previously attempted suicide⁶; 56% have a psychiatric or chronic medical comorbidity. Alcohol and drug abuse were reported among 56% of individuals, and 66% had a criminal history.⁶ Additionally, comorbid psychiatric disorders, especially those of the impulsive and emotionally unstable types, such as borderline and antisocial personality disorder, have been found to play a major role in SBC incidents.¹²

Individual suicide vs SBC

Religious beliefs. The term “religios­ity” is used to define an individual’s idiosyncratic religious belief or personal religious philosophy reconciling the concept of death by suicide and the afterlife. Although there are no studies that specifically reference the relationship between SBC and religiosity, religious belief and affiliation appear to be strong motivating factors. SBC victims might have an idiosyncratic view of religion related death by suicide. Whether suicide is performed while under delusional belief about God, the devil, or being possessed by demons,¹³ or to avoid the moral prohibition of most religious faiths in regard to suicide,⁶ the degree of religiosity in SBC is an important area for future research.

Mr. Z stated that his strong religious faith as an Orthodox Christian motivated the attempted SBC. He tried to provoke the officer to kill him, because as a devout Orthodox Christian, it is against his religious beliefs to kill himself. He reasoned that, because his beliefs preclude him from performing the suicidal act on his own,^6,14 having an officer pull the trigger would relieve him from committing what he perceived as a sin.⁶

Lethal vs danger. Another difference is the level of urgency that individuals create around them when attempting SBC. Homant and Kennedy¹⁵ see this in terms of 2 ideas: lethal and danger. Lethal refers to the degree of harm posed toward the suicidal individual. Danger is the degree of harm posed by the suicidal individual toward others (ie, police officers, bystanders, hostages, family members, a spouse, etc.). SBC often is more dangerous and more lethal than other methods of suicide. SBC individuals might threaten the lives of others to provoke the police into using deadly force, such as aiming or brandishing a gun or weapon at police officers or bystanders, increasing the lethality and dangerousness of the situation. Individuals engaging in SBC might shoot or kill others to create a confrontation with the police in order to be killed in the process (Table¹⁶).

Instrumental vs expressive goals

Mohandie and Meloy⁶ identified 2 primary goals of those involved in SBC events: instrumental and expressive. Individuals in the instrumental category are:

• attempting to escape or avoid the consequences of criminal or shameful actions
• using the forced confrontation with police to reconcile a failed relationship
• hoping to avoid the exclusion clauses of life insurance policies
• rationalizing that while it may be morally wrong to commit suicide, being killed resolves the spiritual problem of suicide
• seeking what they believe to be a very effective and lethal means of accomplishing death.

An expressive goal is more personal and includes individuals who use the confrontation with the police to communicate:

• hopelessness, depression, and desperation
• a statement about their ultimate identification as victims
• their need to “save face” by dying or being forcibly overwhelmed rather than surrendering
• their intense power needs, rage, and revenge
• their need to draw attention to an important personal issue.

Mr. Z chose what he believed to be an efficiently lethal way of dying in accord with his religious faith, knowing that a confrontation with the police could have a fatal ending. This case represents an instrumental motivation to die by SBC that was religiously motivated.

[polldaddy:9731428]

The authors’ observations

SBC presents a specific and serious challenge for law enforcement personnel, and should be approached in a manner different than other crisis situations. Because many individuals engaging in SBC have a history of mental illness, officers with training in handling individuals with psychiatric disorders—known as Crisis Intervention Team (CIT) in many areas—should be deployed as first responders. CITs have been shown to:

• reduce arrest rates of individuals with psychiatric disorders
• increase referral rates to appropriate treatment
• decrease police injuries when responding to calls
• decrease the need for escalation with specialized tactical response teams, such as Special Weapons And Tactics.¹⁷

Identification of SBC behavior is crucial during police response. Indicators of a SBC include:

• refusal to comply with police order
• refusal to surrender
• lack of interest in getting out of a barricade or hostage situation alive.¹⁸

In approaching a SBC incident, responding officers should be non-confrontational and try to talk to the suicidal individual.⁸ If force is needed to resolve the crisis, non-lethal measures should be used first.⁸ Law enforcement and mental health professionals should suspect a SBC situation in individuals who have had prior police contact and are exhibiting behaviors outlined in the Table.¹⁶

Once suicidality is identified, it should be treated promptly. Patients who are at imminent risk to themselves or others should be hospitalized to maintain their safety. Similar to other suicide modalities, the primary risk factor for SBC is untreated or inadequately treated psychiatric illness. Therefore, the crux of managing SBC involves identifying and treating the underlying mental disorder.

Pharmacological treatment should be guided by the patient’s symptoms and psychiatric diagnosis. For suicidal behavior associated with bipolar depression and other affective disorders, lithium has evidence of reducing suicidality. Studies have shown a 5.5-fold reduction in suicide risk and a >13-fold reduction in completed suicides with lithium treatment.¹⁹ In patients with schizophrenia, clozapine has been shown to reduce suicide risk and is the only FDA-approved agent for this indication.¹⁹ Although antidepressants can effectively treat depression, there are no studies that show that 1 antidepressant is more effective than others in reducing suicidality. This might be because of the long latency period between treatment initiation and symptom relief. Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has shown promising results because of its acute effect on depression.²⁰ Because of its rapid symptom relief, ECT remains the standard for treating suicidality related to treatment-resistant depression, psychosis, or mania.²¹

OUTCOME Medication adjustment

After Mr. Z is medically stable, he is voluntarily transferred to the inpatient psychiatric unit where he is stabilized on quetiapine, 200 mg/d, and duloxetine, 60 mg/d, and attends daily group activity, milieu, and individual therapy. Because of Mr. Z’s chronic affective instability and suicidality, we consider lithium for its anti-suicide effects, but decide against it because of lithium’s high lethality in an overdose and Mr. Z’s history of poor compliance and alcohol use.

Because of Mr. Z’s socioeconomic challenges, it is necessary to contact his extended family and social support system to be part of treatment and safety planning. After a week on the psychiatric unit, his mood symptoms stabilize and he is discharged to his family and friends in the area, with a short supply of quetiapine and duloxetine, and free follow-up care within 3 days of discharge. His mood is euthymic; his affect is broad range; his thought process is coherent and logical; he denies suicidal ideation; and can verbalize a logical and concrete safety plan. His support system assures us that Mr. Z will follow up with his appointments.

His DSM-5²² discharge diagnoses are borderline personality disorder, bipolar I disorder, and suicidal behavior disorder, current.

The authors’ observations

SBC increases friction and mistrust between the police and the public, traumatizes officers who are forced to use deadly measures, and results in the death of the suicidal individual. As mental health professionals, we need to be aware of this form of suicide in our screening assessment. Training police to differentiate violent offenders from psychiatric patients could reduce the number of SBCs.⁹ As shown by the CIT model, educating officers on behaviors indicating a mental illness could lead to more psychiatric admissions rather than incarceration¹⁷ or death. We advocate for continuous collaborative work and cross training between the police and mental health professionals and for more research on the link between religiosity and the motivation to die by SBC, because there appears to be a not-yet quantified but strong link between them.

CASE Unresponsive and suicidal

Mr. Z, age 25, an unemployed immigrant from Eastern Europe, is found unresponsive at a subway station. Workup in the emergency room reveals a positive urine toxicology for benzodiazepines and a blood alcohol level of 101.6 mg/dL. When Mr. Z regains consciousness the next day, he says that he is suicidal. He recently broke up with his girlfriend and feels worthless, hopeless, and depressed. As a suicide attempt, he took quetiapine and diazepam chased with vodka.

Mr. Z reports a history of suicide attempts. He says he has been suffering from depression most of his life and has been diagnosed with bipolar I disorder and borderline personality disorder. His medication regimen consists of quetiapine, 200 mg/d, and duloxetine, 20 mg/d.

Before immigrating to the United States 5 years ago, he attempted to overdose on his mother’s prescribed diazepam and was in a coma for 2 days. Recently, he stole a bicycle with the intent of provoking the police to kill him. When caught, he deliberately disobeyed the officer’s order and advanced toward the officer in an aggressive manner. However, the officer stopped Mr. Z using a stun gun. Mr. Z reports that he still feels angry that his suicide attempt failed. He is an Orthodox Christian and says he is “very religious.”

[polldaddy:9731423]

The authors’ observations

The means of suicide differ among individuals. Some attempt suicide by themselves; others through the involuntary participation of others, such as the police. This is known as SBC. Other terms include “suicide by means of victim-precipitated homicide,”¹ “hetero-suicide,”² “suicide by proxy,”³ “copicide,”⁴ and “law enforcement-forced-assisted suicide.”^5,6 SBC accounts for 10%⁷ to 36%⁶ of police shootings and can cause serious stress for the officers involved and creates a strain between the police and the community.⁸

SBC was first mentioned as “suicide by means of victim-precipitated homicide.” Wolfgang⁵ reported 588 cases of police officer-involved shooting in Philadelphia between January 1948 and December 31, 1952, and, concluded that 150 of these cases (26%) fit criteria for what the author termed “victim-precipitated homicide” because the victims involved were the direct precipitants of the situation leading to their death. Wolfgang stated:

Instead of a murderer performing the act of suicide by killing another person who represents the murder’s unconscious, and instead of a suicide representing the desire to kill turned on [the] self, the victim in these victim-precipitated homicide cases is considered to be a suicide prone [individual] who manifests his desire to destroy [him]self by engaging another person to perform the act.

The term “SBC” was coined in 1983 by Karl Harris, a Los Angeles County medical examiner.⁸ The social repercussions of this modality attracts media attention because of its negative social consequences.

Characteristics of SBC

SBC has characteristics similar to other means of suicide; it is more prevalent among men with psychiatric disorders, including major depression, bipolar disorders, schizophrenia, substance use disorders,⁹ poor stress response skills, recent stressors, and adverse life events,¹⁰ and history of suicide attempts.

Psychosocial characteristics include:

• mean age 31.8 years¹
• male sex (98%)
• white (52%)
• approximately 40% involve some form of relationship conflict.⁶

In psychological autopsy studies, an estimated 70.5% of those involved in a SBC incident had ≥1 stressful life events,¹ including terminal illness, loss of a job, a lawsuit, or domestic issues. However, the reason is unknown for the remaining 28% cases.² Thirty-five percent of those involved in SBC incidents were married, 13.5% divorced, and 46.7% single.¹ Seventy-seven percent had low socioeconomic status,¹¹ with 49.3% unemployed at the time of the SBC incident.¹

Pathological characteristics of SBC and other suicide means are similar. Among SBC cases, 39% had previously attempted suicide⁶; 56% have a psychiatric or chronic medical comorbidity. Alcohol and drug abuse were reported among 56% of individuals, and 66% had a criminal history.⁶ Additionally, comorbid psychiatric disorders, especially those of the impulsive and emotionally unstable types, such as borderline and antisocial personality disorder, have been found to play a major role in SBC incidents.¹²

Individual suicide vs SBC

Religious beliefs. The term “religios­ity” is used to define an individual’s idiosyncratic religious belief or personal religious philosophy reconciling the concept of death by suicide and the afterlife. Although there are no studies that specifically reference the relationship between SBC and religiosity, religious belief and affiliation appear to be strong motivating factors. SBC victims might have an idiosyncratic view of religion related death by suicide. Whether suicide is performed while under delusional belief about God, the devil, or being possessed by demons,¹³ or to avoid the moral prohibition of most religious faiths in regard to suicide,⁶ the degree of religiosity in SBC is an important area for future research.

Mr. Z stated that his strong religious faith as an Orthodox Christian motivated the attempted SBC. He tried to provoke the officer to kill him, because as a devout Orthodox Christian, it is against his religious beliefs to kill himself. He reasoned that, because his beliefs preclude him from performing the suicidal act on his own,^6,14 having an officer pull the trigger would relieve him from committing what he perceived as a sin.⁶

Lethal vs danger. Another difference is the level of urgency that individuals create around them when attempting SBC. Homant and Kennedy¹⁵ see this in terms of 2 ideas: lethal and danger. Lethal refers to the degree of harm posed toward the suicidal individual. Danger is the degree of harm posed by the suicidal individual toward others (ie, police officers, bystanders, hostages, family members, a spouse, etc.). SBC often is more dangerous and more lethal than other methods of suicide. SBC individuals might threaten the lives of others to provoke the police into using deadly force, such as aiming or brandishing a gun or weapon at police officers or bystanders, increasing the lethality and dangerousness of the situation. Individuals engaging in SBC might shoot or kill others to create a confrontation with the police in order to be killed in the process (Table¹⁶).

Instrumental vs expressive goals

Mohandie and Meloy⁶ identified 2 primary goals of those involved in SBC events: instrumental and expressive. Individuals in the instrumental category are:

• attempting to escape or avoid the consequences of criminal or shameful actions
• using the forced confrontation with police to reconcile a failed relationship
• hoping to avoid the exclusion clauses of life insurance policies
• rationalizing that while it may be morally wrong to commit suicide, being killed resolves the spiritual problem of suicide
• seeking what they believe to be a very effective and lethal means of accomplishing death.

An expressive goal is more personal and includes individuals who use the confrontation with the police to communicate:

• hopelessness, depression, and desperation
• a statement about their ultimate identification as victims
• their need to “save face” by dying or being forcibly overwhelmed rather than surrendering
• their intense power needs, rage, and revenge
• their need to draw attention to an important personal issue.

Mr. Z chose what he believed to be an efficiently lethal way of dying in accord with his religious faith, knowing that a confrontation with the police could have a fatal ending. This case represents an instrumental motivation to die by SBC that was religiously motivated.

[polldaddy:9731428]

The authors’ observations

SBC presents a specific and serious challenge for law enforcement personnel, and should be approached in a manner different than other crisis situations. Because many individuals engaging in SBC have a history of mental illness, officers with training in handling individuals with psychiatric disorders—known as Crisis Intervention Team (CIT) in many areas—should be deployed as first responders. CITs have been shown to:

• reduce arrest rates of individuals with psychiatric disorders
• increase referral rates to appropriate treatment
• decrease police injuries when responding to calls
• decrease the need for escalation with specialized tactical response teams, such as Special Weapons And Tactics.¹⁷

Identification of SBC behavior is crucial during police response. Indicators of a SBC include:

• refusal to comply with police order
• refusal to surrender
• lack of interest in getting out of a barricade or hostage situation alive.¹⁸

In approaching a SBC incident, responding officers should be non-confrontational and try to talk to the suicidal individual.⁸ If force is needed to resolve the crisis, non-lethal measures should be used first.⁸ Law enforcement and mental health professionals should suspect a SBC situation in individuals who have had prior police contact and are exhibiting behaviors outlined in the Table.¹⁶

Once suicidality is identified, it should be treated promptly. Patients who are at imminent risk to themselves or others should be hospitalized to maintain their safety. Similar to other suicide modalities, the primary risk factor for SBC is untreated or inadequately treated psychiatric illness. Therefore, the crux of managing SBC involves identifying and treating the underlying mental disorder.

Pharmacological treatment should be guided by the patient’s symptoms and psychiatric diagnosis. For suicidal behavior associated with bipolar depression and other affective disorders, lithium has evidence of reducing suicidality. Studies have shown a 5.5-fold reduction in suicide risk and a >13-fold reduction in completed suicides with lithium treatment.¹⁹ In patients with schizophrenia, clozapine has been shown to reduce suicide risk and is the only FDA-approved agent for this indication.¹⁹ Although antidepressants can effectively treat depression, there are no studies that show that 1 antidepressant is more effective than others in reducing suicidality. This might be because of the long latency period between treatment initiation and symptom relief. Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has shown promising results because of its acute effect on depression.²⁰ Because of its rapid symptom relief, ECT remains the standard for treating suicidality related to treatment-resistant depression, psychosis, or mania.²¹

OUTCOME Medication adjustment

After Mr. Z is medically stable, he is voluntarily transferred to the inpatient psychiatric unit where he is stabilized on quetiapine, 200 mg/d, and duloxetine, 60 mg/d, and attends daily group activity, milieu, and individual therapy. Because of Mr. Z’s chronic affective instability and suicidality, we consider lithium for its anti-suicide effects, but decide against it because of lithium’s high lethality in an overdose and Mr. Z’s history of poor compliance and alcohol use.

Because of Mr. Z’s socioeconomic challenges, it is necessary to contact his extended family and social support system to be part of treatment and safety planning. After a week on the psychiatric unit, his mood symptoms stabilize and he is discharged to his family and friends in the area, with a short supply of quetiapine and duloxetine, and free follow-up care within 3 days of discharge. His mood is euthymic; his affect is broad range; his thought process is coherent and logical; he denies suicidal ideation; and can verbalize a logical and concrete safety plan. His support system assures us that Mr. Z will follow up with his appointments.

His DSM-5²² discharge diagnoses are borderline personality disorder, bipolar I disorder, and suicidal behavior disorder, current.

The authors’ observations

SBC increases friction and mistrust between the police and the public, traumatizes officers who are forced to use deadly measures, and results in the death of the suicidal individual. As mental health professionals, we need to be aware of this form of suicide in our screening assessment. Training police to differentiate violent offenders from psychiatric patients could reduce the number of SBCs.⁹ As shown by the CIT model, educating officers on behaviors indicating a mental illness could lead to more psychiatric admissions rather than incarceration¹⁷ or death. We advocate for continuous collaborative work and cross training between the police and mental health professionals and for more research on the link between religiosity and the motivation to die by SBC, because there appears to be a not-yet quantified but strong link between them.

CASE Unresponsive and suicidal

Mr. Z, age 25, an unemployed immigrant from Eastern Europe, is found unresponsive at a subway station. Workup in the emergency room reveals a positive urine toxicology for benzodiazepines and a blood alcohol level of 101.6 mg/dL. When Mr. Z regains consciousness the next day, he says that he is suicidal. He recently broke up with his girlfriend and feels worthless, hopeless, and depressed. As a suicide attempt, he took quetiapine and diazepam chased with vodka.

Mr. Z reports a history of suicide attempts. He says he has been suffering from depression most of his life and has been diagnosed with bipolar I disorder and borderline personality disorder. His medication regimen consists of quetiapine, 200 mg/d, and duloxetine, 20 mg/d.

Before immigrating to the United States 5 years ago, he attempted to overdose on his mother’s prescribed diazepam and was in a coma for 2 days. Recently, he stole a bicycle with the intent of provoking the police to kill him. When caught, he deliberately disobeyed the officer’s order and advanced toward the officer in an aggressive manner. However, the officer stopped Mr. Z using a stun gun. Mr. Z reports that he still feels angry that his suicide attempt failed. He is an Orthodox Christian and says he is “very religious.”

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The authors’ observations

The means of suicide differ among individuals. Some attempt suicide by themselves; others through the involuntary participation of others, such as the police. This is known as SBC. Other terms include “suicide by means of victim-precipitated homicide,”¹ “hetero-suicide,”² “suicide by proxy,”³ “copicide,”⁴ and “law enforcement-forced-assisted suicide.”^5,6 SBC accounts for 10%⁷ to 36%⁶ of police shootings and can cause serious stress for the officers involved and creates a strain between the police and the community.⁸

SBC was first mentioned as “suicide by means of victim-precipitated homicide.” Wolfgang⁵ reported 588 cases of police officer-involved shooting in Philadelphia between January 1948 and December 31, 1952, and, concluded that 150 of these cases (26%) fit criteria for what the author termed “victim-precipitated homicide” because the victims involved were the direct precipitants of the situation leading to their death. Wolfgang stated:

Instead of a murderer performing the act of suicide by killing another person who represents the murder’s unconscious, and instead of a suicide representing the desire to kill turned on [the] self, the victim in these victim-precipitated homicide cases is considered to be a suicide prone [individual] who manifests his desire to destroy [him]self by engaging another person to perform the act.

The term “SBC” was coined in 1983 by Karl Harris, a Los Angeles County medical examiner.⁸ The social repercussions of this modality attracts media attention because of its negative social consequences.

Characteristics of SBC

SBC has characteristics similar to other means of suicide; it is more prevalent among men with psychiatric disorders, including major depression, bipolar disorders, schizophrenia, substance use disorders,⁹ poor stress response skills, recent stressors, and adverse life events,¹⁰ and history of suicide attempts.

Psychosocial characteristics include:

• mean age 31.8 years¹
• male sex (98%)
• white (52%)
• approximately 40% involve some form of relationship conflict.⁶

In psychological autopsy studies, an estimated 70.5% of those involved in a SBC incident had ≥1 stressful life events,¹ including terminal illness, loss of a job, a lawsuit, or domestic issues. However, the reason is unknown for the remaining 28% cases.² Thirty-five percent of those involved in SBC incidents were married, 13.5% divorced, and 46.7% single.¹ Seventy-seven percent had low socioeconomic status,¹¹ with 49.3% unemployed at the time of the SBC incident.¹

Pathological characteristics of SBC and other suicide means are similar. Among SBC cases, 39% had previously attempted suicide⁶; 56% have a psychiatric or chronic medical comorbidity. Alcohol and drug abuse were reported among 56% of individuals, and 66% had a criminal history.⁶ Additionally, comorbid psychiatric disorders, especially those of the impulsive and emotionally unstable types, such as borderline and antisocial personality disorder, have been found to play a major role in SBC incidents.¹²

Individual suicide vs SBC

Religious beliefs. The term “religios­ity” is used to define an individual’s idiosyncratic religious belief or personal religious philosophy reconciling the concept of death by suicide and the afterlife. Although there are no studies that specifically reference the relationship between SBC and religiosity, religious belief and affiliation appear to be strong motivating factors. SBC victims might have an idiosyncratic view of religion related death by suicide. Whether suicide is performed while under delusional belief about God, the devil, or being possessed by demons,¹³ or to avoid the moral prohibition of most religious faiths in regard to suicide,⁶ the degree of religiosity in SBC is an important area for future research.

Mr. Z stated that his strong religious faith as an Orthodox Christian motivated the attempted SBC. He tried to provoke the officer to kill him, because as a devout Orthodox Christian, it is against his religious beliefs to kill himself. He reasoned that, because his beliefs preclude him from performing the suicidal act on his own,^6,14 having an officer pull the trigger would relieve him from committing what he perceived as a sin.⁶

Lethal vs danger. Another difference is the level of urgency that individuals create around them when attempting SBC. Homant and Kennedy¹⁵ see this in terms of 2 ideas: lethal and danger. Lethal refers to the degree of harm posed toward the suicidal individual. Danger is the degree of harm posed by the suicidal individual toward others (ie, police officers, bystanders, hostages, family members, a spouse, etc.). SBC often is more dangerous and more lethal than other methods of suicide. SBC individuals might threaten the lives of others to provoke the police into using deadly force, such as aiming or brandishing a gun or weapon at police officers or bystanders, increasing the lethality and dangerousness of the situation. Individuals engaging in SBC might shoot or kill others to create a confrontation with the police in order to be killed in the process (Table¹⁶).

Instrumental vs expressive goals

Mohandie and Meloy⁶ identified 2 primary goals of those involved in SBC events: instrumental and expressive. Individuals in the instrumental category are:

• attempting to escape or avoid the consequences of criminal or shameful actions
• using the forced confrontation with police to reconcile a failed relationship
• hoping to avoid the exclusion clauses of life insurance policies
• rationalizing that while it may be morally wrong to commit suicide, being killed resolves the spiritual problem of suicide
• seeking what they believe to be a very effective and lethal means of accomplishing death.

An expressive goal is more personal and includes individuals who use the confrontation with the police to communicate:

• hopelessness, depression, and desperation
• a statement about their ultimate identification as victims
• their need to “save face” by dying or being forcibly overwhelmed rather than surrendering
• their intense power needs, rage, and revenge
• their need to draw attention to an important personal issue.

Mr. Z chose what he believed to be an efficiently lethal way of dying in accord with his religious faith, knowing that a confrontation with the police could have a fatal ending. This case represents an instrumental motivation to die by SBC that was religiously motivated.

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The authors’ observations

SBC presents a specific and serious challenge for law enforcement personnel, and should be approached in a manner different than other crisis situations. Because many individuals engaging in SBC have a history of mental illness, officers with training in handling individuals with psychiatric disorders—known as Crisis Intervention Team (CIT) in many areas—should be deployed as first responders. CITs have been shown to:

• reduce arrest rates of individuals with psychiatric disorders
• increase referral rates to appropriate treatment
• decrease police injuries when responding to calls
• decrease the need for escalation with specialized tactical response teams, such as Special Weapons And Tactics.¹⁷

Identification of SBC behavior is crucial during police response. Indicators of a SBC include:

• refusal to comply with police order
• refusal to surrender
• lack of interest in getting out of a barricade or hostage situation alive.¹⁸

In approaching a SBC incident, responding officers should be non-confrontational and try to talk to the suicidal individual.⁸ If force is needed to resolve the crisis, non-lethal measures should be used first.⁸ Law enforcement and mental health professionals should suspect a SBC situation in individuals who have had prior police contact and are exhibiting behaviors outlined in the Table.¹⁶

Once suicidality is identified, it should be treated promptly. Patients who are at imminent risk to themselves or others should be hospitalized to maintain their safety. Similar to other suicide modalities, the primary risk factor for SBC is untreated or inadequately treated psychiatric illness. Therefore, the crux of managing SBC involves identifying and treating the underlying mental disorder.

Pharmacological treatment should be guided by the patient’s symptoms and psychiatric diagnosis. For suicidal behavior associated with bipolar depression and other affective disorders, lithium has evidence of reducing suicidality. Studies have shown a 5.5-fold reduction in suicide risk and a >13-fold reduction in completed suicides with lithium treatment.¹⁹ In patients with schizophrenia, clozapine has been shown to reduce suicide risk and is the only FDA-approved agent for this indication.¹⁹ Although antidepressants can effectively treat depression, there are no studies that show that 1 antidepressant is more effective than others in reducing suicidality. This might be because of the long latency period between treatment initiation and symptom relief. Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has shown promising results because of its acute effect on depression.²⁰ Because of its rapid symptom relief, ECT remains the standard for treating suicidality related to treatment-resistant depression, psychosis, or mania.²¹

OUTCOME Medication adjustment

After Mr. Z is medically stable, he is voluntarily transferred to the inpatient psychiatric unit where he is stabilized on quetiapine, 200 mg/d, and duloxetine, 60 mg/d, and attends daily group activity, milieu, and individual therapy. Because of Mr. Z’s chronic affective instability and suicidality, we consider lithium for its anti-suicide effects, but decide against it because of lithium’s high lethality in an overdose and Mr. Z’s history of poor compliance and alcohol use.

Because of Mr. Z’s socioeconomic challenges, it is necessary to contact his extended family and social support system to be part of treatment and safety planning. After a week on the psychiatric unit, his mood symptoms stabilize and he is discharged to his family and friends in the area, with a short supply of quetiapine and duloxetine, and free follow-up care within 3 days of discharge. His mood is euthymic; his affect is broad range; his thought process is coherent and logical; he denies suicidal ideation; and can verbalize a logical and concrete safety plan. His support system assures us that Mr. Z will follow up with his appointments.

His DSM-5²² discharge diagnoses are borderline personality disorder, bipolar I disorder, and suicidal behavior disorder, current.

The authors’ observations

SBC increases friction and mistrust between the police and the public, traumatizes officers who are forced to use deadly measures, and results in the death of the suicidal individual. As mental health professionals, we need to be aware of this form of suicide in our screening assessment. Training police to differentiate violent offenders from psychiatric patients could reduce the number of SBCs.⁹ As shown by the CIT model, educating officers on behaviors indicating a mental illness could lead to more psychiatric admissions rather than incarceration¹⁷ or death. We advocate for continuous collaborative work and cross training between the police and mental health professionals and for more research on the link between religiosity and the motivation to die by SBC, because there appears to be a not-yet quantified but strong link between them.

More than 29 million Americans have diabetes, and each year another 1.7 million are given the diagnosis.¹ Prediabetes is even more common; over one-third of US adults ages 20 years and older, and more than half of those who are ages 65 and older, have attained this precursor status, representing another 86 million Americans.¹

Because the evidence base for the management of diabetes is rapidly expanding, the American Diabetes Association’s (ADA) Professional Practice Committee updates its Standards of Medical Care in Diabetes annually to incorporate new evidence into its recommendations. The 2017 Standards of Care are available at: professional.diabetes.org/jfp.²

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality for people with diabetes, and is the largest contributor to the direct and indirect costs of the disease.² As a result, all patients with diabetes should have cardiovascular (CV) risk factors, including dyslipidemia, hypertension, smoking, a family history of premature coronary disease, and the presence of albuminuria, assessed at least annually.² Numerous studies have demonstrated the efficacy of controlling individual CV risk factors in preventing or slowing ASCVD in people with diabetes. Even larger benefits, including reduced ASCVD morbidity and mortality, can be achieved when multiple risk factors are addressed simultaneously.³

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for the 29 million Americans with diabetes, and is the largest contributor to the direct and indirect costs of diabetes.

To hone your management of CV risks in patients with diabetes, we’ve put together this Q&A pointing out the elements of the ADA’s 2017 Standards of Care that are most relevant to the management of patients at risk for, or with established, ASCVD.

Screening

Since ASCVD so commonly co-occurs with diabetes, should I routinely screen asymptomatic patients with diabetes for heart disease?

No. The current evidence suggests that outcomes are NOT improved by screening people before they develop symptoms of ASCVD,⁴ and widespread ASCVD screening has not been shown to be cost-effective. Cardiac testing should be reserved for those with typical or atypical symptoms or those with an abnormal resting electrocardiogram (EKG).

Lifestyle modification

What are the benefits of lifestyle interventions?

The benefits include not only lost pounds, but improved mobility, physical and sexual functioning, and health-related quality of life. Recommend that all overweight patients with diabetes take advantage of intensive lifestyle interventions focusing on weight loss through decreased caloric intake and increased physical activity as per the Look AHEAD (Action for Health in Diabetes) trial.⁵ Although the intensive lifestyle intervention in the Look AHEAD trial did not decrease CV outcomes over 10 years of follow-up, it did improve control of CV risk factors and led to people in the intervention group taking fewer glucose-, blood pressure (BP)-, and lipid-lowering medications than those in the standard care group.

There is no one diet that is recommended for all people with diabetes. Weight reduction often requires intensive intervention. In order for weight loss diets to be sustainable, they must include patient preferences.

People with diabetes should be encouraged to receive individualized medical nutrition therapy (MNT), preferably from a registered dietitian who is well versed in nutritional management for diabetes. Such MNT is associated with a 0.5% to 2% decrease in A1c levels for people with type 2 diabetes.^6-9 Specific healthy diets include the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and plant-based diets.

A new lifestyle recommendation in this year’s ADA Standards is that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity. This appears to have glycemic benefits.²

Hypertension/BP management

When should I initiate hypertension treatment in patients with diabetes?

Nonpharmacologic therapy is reasonable in people with diabetes and mildly elevated BP (>120/80 mm Hg). If systolic blood pressure (SBP) is confirmed to be >140 mm Hg and/or diastolic blood pressure (DBP) is confirmed to be >90 mm Hg, the ADA recommends initiating pharmacologic therapy along with nonpharmacologic strategies. For patients with confirmed office-based BP >160/100 mm Hg, the ADA advises initiating lifestyle modifications as well as 2 pharmacologic medications (or a single pill combination of agents).²

What is the recommended BP target for patients with diabetes and hypertension?

These patients should be treated with a combination of measures, including lifestyle modification and pharmacologic therapy, to a target BP of <140/90 mm Hg. Randomized controlled trials (RCTs) have shown benefits with this target in terms of a reduction in the incidence of coronary heart disease (CHD) events, stroke, and diabetic kidney disease.^10,11

A 2012 meta-analysis of randomized trials involving adults with type 2 diabetes mellitus (T2DM) and comparing intensive BP targets (≤130 mm Hg SBP and ≤80 mm Hg DBP) with standard targets (≤140-160 mm Hg SBP and ≤85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MIs associated with more intense BP control. There was a statistically significant 35% relative risk (RR) reduction in stroke with intensive targets, but lower BP was also associated with an increased risk of hypotension and syncope.¹²

A new lifestyle recommendation in this year’s ADA Standards states that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity.

The 2010 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹³ which randomized 5518 patients with T2DM at high risk for ASCVD to either a target SBP of <120 mm Hg or 130 to 140 mm Hg, found that the patients with the lower SBP target did not benefit in the primary end point (a composite of nonfatal MI, nonfatal stroke, and CV death), but did benefit from nominally significant lower rates of total stroke and nonfatal stroke.

Based on these data, the ADA Standards of Care suggest that, “more intensive BP control may be reasonable in certain motivated, ACCORD-like patients (40-79 years of age with prior evidence of CVD or multiple CV risk factors) who have been educated about the added treatment burden, side effects, and costs of more intensive BP control and for patients who prefer to lower their risk of stroke beyond what can be achieved with usual care.”

Another major study, the 2015 Systolic Blood Pressure Intervention Trial (SPRINT) trial,¹⁴ demonstrated that treating patients with hypertension to a target SBP <120 mm Hg compared to the usual target of <140 mm Hg resulted in a 25% lower RR of the primary outcome (a composite of MI, other acute coronary syndromes, stroke, heart failure, or death from CV causes) and about a 25% reduction in all-cause mortality; however, people with diabetes were not included in the trial, so the applicability of the results to decisions about BP management in patients with diabetes is not known.

In people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.

A 2015 systematic review and meta-analysis of over 100,000 participants looked at SBP lowering in adults with T2DM and found that each 10-mm Hg reduction in SBP was associated with a significantly lower risk of morbidity, CV events, CHD, stroke, albuminuria, and retinopathy.¹⁰ When trials were stratified by mean baseline SBP (<140 mm Hg or ≥140 mm Hg), RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline SBP.

The latest ADA Standards of Care recommend that a lower BP target of 130/80 mm Hg may be appropriate for patients at high risk of CVD if this target can be achieved without undue treatment burden. A DBP of <80 mm Hg may also be appropriate in certain patients including those with a long life expectancy, CKD, elevated urinary albumin excretion, and those with evidence of CVD or associated risk factors.¹⁵ Of note, treating older adults with diabetes to an SBP target of <130 mm Hg has not been shown to improve cardiovascular outcomes,¹⁶ and treating to a diastolic target of <70 mm Hg has been associated with a greater risk of mortality.¹⁷

What are the current recommended treatment options?

Treatment for hypertension in adults with diabetes without albuminuria should include any of the classes of medications demonstrated to reduce CV events in patients with diabetes, such as:

• angiotensin-converting enzyme (ACE) inhibitors,
• angiotensin receptor blockers (ARBs),
• thiazide-like diuretics, and
• dihydropyridine calcium channel blockers.

These recommendations are based on evidence suggesting the lack of superiority of ACE inhibitors and ARBs over other classes of antihypertensive agents for the prevention of CV outcomes in all patients with diabetes.¹⁸ However, in people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.^19-24 Thus, ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and urine albumin/creatinine ratios ≥30 mg/g, as these medications are associated with a reduction in the rate of kidney disease progression.

The use of both an ACE inhibitor and an ARB in combination is not recommended.^25,26 For patients treated with ACE inhibitors, ARBs, or diuretics, serum creatinine/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored.

What are the recommended lifestyle modifications for patients with diabetes and hypertension?

Regular exercise and healthy eating are recommended for all people with diabetes to optimize glycemic control and lose weight (if they are overweight or obese). For patients with hypertension, the DASH diet (available at: https://www.nhlbi.nih.gov/health/health-topics/topics/dash/) is effective at lowering BP. The DASH diet emphasizes reducing sodium intake, increasing potassium intake, limiting alcohol intake, and increasing physical activity. Specifically, sodium intake should be restricted to <2300 mg/d and patients should consume approximately 8 to 10 servings of fruits and vegetables per day and 2 to 3 servings of low-fat dairy per day. Alcohol should be limited to 2 drinks per day for men and one drink per day for women.

People with diabetes who have hypertension should be treated with lifestyle modification and pharmacologic therapy to a target blood pressure of <140/90 mm Hg.

Most adults with diabetes should perform 150 minutes per week of moderate to vigorous exercise, spread over at least 3 days/week. In addition, it is recommended that resistance exercises be performed at least 2 to 3 days/week. Prolonged inactivity is detrimental to health and should be interrupted with activity every 30 minutes.²⁷

Finally, as a part of lifestyle management for all patients with diabetes, smoking cessation is important, as is attention to stress, depression, and anxiety.

Is there an advantage to nighttime dosing of antihypertensive medications?

Yes. Growing evidence suggests that there is an ASCVD benefit to avoiding nocturnal BP dipping. A 2011 RCT of 448 participants with T2DM and hypertension showed a decrease in CV events and mortality during 5.4 years of follow-up if at least one antihypertensive medication was taken at bedtime.²⁸ As a result of this and other evidence,²⁹ consider administering one or more antihypertensive medications at bedtime, although this is not a formal recommendation in the ADA Standards of Care.

Are there any additional issues to be aware of when treating patients with diabetes and hypertension?

Yes. Sometimes patients who have had diabetes for many years have significant orthostatic hypotension secondary to autonomic neuropathy. Postural changes in BP and pulse may require adjustment of BP targets. Home BP self-monitoring and 24-hour ambulatory BP monitoring may indicate white-coat or masked hypertension.

Lipid management

What is the current evidence for lipid treatment in diabetes?

Lipid abnormalities are common in people with diabetes and contribute to the overall high risk of ASCVD in these patients. Subgroup analyses of patients in large trials with diabetes³⁰ and trials involving patients with diabetes³¹ have shown significant improvements in primary and secondary prevention of ASCVD with statin use. A 2008 meta-analysis of 18,686 people with diabetes showed a 9% reduction in all-cause mortality and a 13% reduction in vascular mortality for each 39-mg/dL reduction in low-density lipoprotein (LDL) cholesterol.³² Absolute reductions in mortality are greatest in those with highest risk, but the benefits of statin therapy are clear for low- and moderate-risk individuals with diabetes, too.^33,34 As a result, statins are the medications of choice for lipid lowering and CV risk reduction and should be used in addition to lifestyle management.

Who should get a statin, and how do I choose the optimum dosage?

Patients ages 40 to 75 years with diabetes but without additional ASCVD risk factors should receive a moderate-intensity statin, according to the ADA (see TABLES 1² and 2²). For those with additional CV risk factors, a high-intensity statin should be considered. The American College of Cardiology/American Heart Association ASCVD risk calculator (available at: http://www.cvriskcalculator.com/) may be useful for some patients, but generally, risk is already known to be high for most patients with diabetes. For patients of all ages with diabetes and established ASCVD, high-intensity statin therapy should be added to lifestyle modifications.^35-37

For patients with diabetes who are <40 years with additional ASCVD risk factors, few clinical trial data exist; nevertheless, consider a moderate- or high-intensity statin and lifestyle therapy. Similarly, for patients >75 years who have diabetes and no additional ASCVD risk factors, consider a moderate-intensity statin and lifestyle modifications. For older adults with additional ASCVD risk factors, consider high-intensity statin therapy.^35-37

Statins and cognition. It should be noted that published data have not demonstrated an adverse effect of statins on cognition.³⁸ Statins, however, have been linked to an increased risk of developing diabetes,^39,40 although the absolute increase in risk is small, and much smaller than the benefit derived from preventing the development of coronary disease.

Should total cholesterol and LDL levels be used as targets with statin treatment?

No. Statin doses have primarily been tested against placebo in clinical trials, rather than testing to specific target LDL levels, suggesting that the initiation and intensification of statin therapy be based on a patient’s risk profile.³⁵ When maximally tolerated doses of statins do not lower LDL cholesterol by more than 30% from the patient’s baseline, there is currently no good evidence that combination therapy would be helpful, so regular monitoring of lipid levels has limited value. A lipid profile that includes levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides should be obtained at initial medical evaluation, at diagnosis of diabetes, and every 5 years thereafter or before the initiation of statin therapy. Ongoing testing may be appropriate in individual circumstances and to monitor for adherence to, or efficacy of, therapy.

What should I do for my patients who can’t tolerate statins?

Try a lower dose or a different statin before eliminating the class. Research has shown that even small doses (eg, rosuvastatin 5 mg) have some benefit.⁴¹

How do combination treatments figure into the current treatment of lipids in patients with diabetes?

It depends on the agent and the patient’s profile.

Fenofibrate. The ADA does not recommend automatically adding fenofibrate to statin therapy because the combination is associated with increased risks for abnormal transaminase levels, myositis, and rhabdomyolysis. In the ACCORD trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, nonfatal MIs, or nonfatal strokes compared with simvastatin alone.⁴²

Recommend statin therapy to all patients with diabetes over age 40; use a moderate- or high-intensity agent depending upon the degree of cardiac risk.

That said, a subgroup analysis suggested a benefit for men with both a triglyceride level ≥204 mg/dL (2.3 mmol/L) and an HDL cholesterol level ≤34 mg/dL (0.9 mmol/L).⁴² For this reason, the combination of a statin and fenofibrate may be considered for men who meet these laboratory parameters. In addition, consider medical therapy for triglyceride levels ≥500 mg/dL to reduce the risk of pancreatitis.

Ezetimibe. Recommendations regarding ezetimibe are based on the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), a 2015 RCT including over 18,000 patients that compared treatment with ezetimibe and simvastatin to simvastatin alone.⁴³ Individuals in the trial were ≥50 years of age and had experienced an ACS within the preceding 10 days. In those with diabetes, the combination of moderate-intensity simvastatin (40 mg) and ezetimibe (10 mg) significantly reduced major adverse CV events with an absolute risk reduction of 5% (40% vs 45%) and an RR reduction of 14% over moderate-intensity simvastatin (40 mg) alone.

Based on these results, patients with diabetes and a recent ACS should be considered for combination therapy with ezetimibe and a moderate-intensity statin. The combination should also be considered in patients with diabetes and a history of ASCVD who cannot tolerate high-intensity statins.⁴³

Recommend daily aspirin therapy to patients ages ≥50 years who have diabetes and at least one additional cardiovascular risk factor, but no bleeding risk.

Niacin. The ADA currently does not recommend niacin in combination with a statin because of lack of efficacy on major ASCVD outcomes, possible increased risk of ischemic stroke, and adverse effects.⁴⁴

What are the recommendations for the use of PCSK-9 inhibitors?

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors (ie, evolucumab and alirocumab) may be considered as adjunctive therapy to statins for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol. They may also be considered for those in whom high-intensity statin therapy is indicated, but not tolerated.

Antiplatelet agents

Who should take aspirin for primary prevention of CVD?

Both women and men ages ≥50 years who have diabetes and at least one additional CV risk factor (family history of premature ASCVD, hypertension, tobacco use, dyslipidemia, or albuminuria) should consider taking daily aspirin therapy (75-162 mg/d) if they do not have an excessive bleeding risk.^45,46 The most common dose in the United States is 81 mg. This recommendation is supported by a 2010 consensus statement of the American Diabetes Association, American Heart Association, and the American College of Cardiology.⁴⁷

Should patients with diabetes and heart disease receive antiplatelet therapy?

Yes. The evidence is clear that people with known diabetes and ASCVD benefit from aspirin therapy, according to the 2017 Standards of Care. Clopidogrel 75 mg/d is an appropriate alternative for patients who are allergic to aspirin. Dual antiplatelet therapy (a P2Y12 receptor antagonist and aspirin) should be used for as long as one year after an ACS and may have benefits beyond this period.⁴⁸

Established heart disease

Are there specific recommendations for patients with diabetes and CHD?

According to the ADA Standards, there is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used. In addition, consider ACE inhibitors to reduce the future risk of CV events. In patients with a prior MI, continue beta-blocker therapy for at least 2 years post event.⁴⁹

Which medications should I avoid, or approach with caution, in patients with congestive heart failure (CHF)?

Thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, and metformin all require careful attention. This is especially important to know when you consider that almost half of all patients with T2DM will develop heart failure.⁵⁰

Thiazolidinediones. The 2017 Standards of Care state that patients with diabetes and symptomatic congestive heart failure should not receive thiazolidinediones, as they can worsen heart failure status via fluid retention. As such, they are contraindicated in patients with class III and IV heart failure.⁵¹

DPP-4 inhibitors. The studies on DPP-4 inhibitors and heart failure have had mixed results. The 2013 SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction) 53 trial⁵² showed that patients treated with saxagliptin were more likely to be hospitalized for heart failure than those taking placebo (3.5% vs 2.8%, respectively). However, the 2015 EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care)⁵³ trial and the 2015 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)⁵⁴ trial evaluated heart failure and mortality outcomes in patients with alogliptin and sitagliptin, respectively, compared to placebo, and did not show a relationship to heart failure.

Metformin may be used in people who have T2DM and stable CHF if their eGFR remains >30 mL/min; it should be withheld from patients with unstable heart failure and those who are hospitalized with CHF.

Are there antihyperglycemic medications that reduce CV morbidity and mortality in those with established ASCVD?

Yes. This year’s ADA Standards indicate that certain glucose-lowering medications—specifically empagliflozin (a sodium–glucose cotransporter [SGLT]-2 inhibitor) and liraglutide (a glucagon-like peptide [GLP]-1 receptor agonist)—have been shown to be beneficial for those with established CVD. According to the 2017 Standards of Care, “In patients with longstanding suboptimally controlled T2DM and established ASCVD, empagliflozin or liraglutide should be considered, as they have been shown to reduce CV and all-cause mortality when added to standard care.”² The studies that provide support for their use are summarized below. Ongoing studies are investigating the CV effects of other agents in these drug classes.

There is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used.

Empagliflozin. The 2015 EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study⁵⁵ was a randomized double-blind study of empagliflozin vs placebo and usual care in patients with diabetes and established CVD. Over a median follow-up of 3.1 years, treatment with empagliflozin reduced the aggregate outcome of MI, stroke, and CV death by 14%, reduced CV deaths by 38%, and decreased deaths from any cause by 32%. In December 2016, the FDA announced a new indication for empagliflozin: to reduce the risk of CV death in adult patients with T2DM and CVD.⁵⁶

Liraglutide. The LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results: A Long Term Evaluation) trial⁵⁷ was a double-blind randomized trial of liraglutide vs placebo added to usual care in patients with T2DM at high risk for CVD or with existing CVD. More than 80% of the participants had existing CVD including a history of prior MI, cerebrovascular disease, or peripheral vascular disease. After a median follow-up of 3.8 years, the group taking liraglutide demonstrated a 13% reduction in the composite outcome of MI, stroke, or CV death, a 22% reduction in CV death, and a 15% reduction in death from any cause, compared with placebo.⁵⁷

CORRESPONDENCE
Neil Skolnik, MD, Abington-Jefferson Health, 500 Old York Rd, Ste 108, Jenkintown, PA 19046; [email protected].

The authors thank Sarah Bradley, director, professional engagement & collaboration at the American Diabetes Association, for her editorial and organizational assistance in the preparation of this manuscript.

More than 29 million Americans have diabetes, and each year another 1.7 million are given the diagnosis.¹ Prediabetes is even more common; over one-third of US adults ages 20 years and older, and more than half of those who are ages 65 and older, have attained this precursor status, representing another 86 million Americans.¹

Because the evidence base for the management of diabetes is rapidly expanding, the American Diabetes Association’s (ADA) Professional Practice Committee updates its Standards of Medical Care in Diabetes annually to incorporate new evidence into its recommendations. The 2017 Standards of Care are available at: professional.diabetes.org/jfp.²

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality for people with diabetes, and is the largest contributor to the direct and indirect costs of the disease.² As a result, all patients with diabetes should have cardiovascular (CV) risk factors, including dyslipidemia, hypertension, smoking, a family history of premature coronary disease, and the presence of albuminuria, assessed at least annually.² Numerous studies have demonstrated the efficacy of controlling individual CV risk factors in preventing or slowing ASCVD in people with diabetes. Even larger benefits, including reduced ASCVD morbidity and mortality, can be achieved when multiple risk factors are addressed simultaneously.³

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for the 29 million Americans with diabetes, and is the largest contributor to the direct and indirect costs of diabetes.

To hone your management of CV risks in patients with diabetes, we’ve put together this Q&A pointing out the elements of the ADA’s 2017 Standards of Care that are most relevant to the management of patients at risk for, or with established, ASCVD.

Screening

Since ASCVD so commonly co-occurs with diabetes, should I routinely screen asymptomatic patients with diabetes for heart disease?

No. The current evidence suggests that outcomes are NOT improved by screening people before they develop symptoms of ASCVD,⁴ and widespread ASCVD screening has not been shown to be cost-effective. Cardiac testing should be reserved for those with typical or atypical symptoms or those with an abnormal resting electrocardiogram (EKG).

Lifestyle modification

What are the benefits of lifestyle interventions?

The benefits include not only lost pounds, but improved mobility, physical and sexual functioning, and health-related quality of life. Recommend that all overweight patients with diabetes take advantage of intensive lifestyle interventions focusing on weight loss through decreased caloric intake and increased physical activity as per the Look AHEAD (Action for Health in Diabetes) trial.⁵ Although the intensive lifestyle intervention in the Look AHEAD trial did not decrease CV outcomes over 10 years of follow-up, it did improve control of CV risk factors and led to people in the intervention group taking fewer glucose-, blood pressure (BP)-, and lipid-lowering medications than those in the standard care group.

There is no one diet that is recommended for all people with diabetes. Weight reduction often requires intensive intervention. In order for weight loss diets to be sustainable, they must include patient preferences.

People with diabetes should be encouraged to receive individualized medical nutrition therapy (MNT), preferably from a registered dietitian who is well versed in nutritional management for diabetes. Such MNT is associated with a 0.5% to 2% decrease in A1c levels for people with type 2 diabetes.^6-9 Specific healthy diets include the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and plant-based diets.

A new lifestyle recommendation in this year’s ADA Standards is that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity. This appears to have glycemic benefits.²

Hypertension/BP management

When should I initiate hypertension treatment in patients with diabetes?

Nonpharmacologic therapy is reasonable in people with diabetes and mildly elevated BP (>120/80 mm Hg). If systolic blood pressure (SBP) is confirmed to be >140 mm Hg and/or diastolic blood pressure (DBP) is confirmed to be >90 mm Hg, the ADA recommends initiating pharmacologic therapy along with nonpharmacologic strategies. For patients with confirmed office-based BP >160/100 mm Hg, the ADA advises initiating lifestyle modifications as well as 2 pharmacologic medications (or a single pill combination of agents).²

What is the recommended BP target for patients with diabetes and hypertension?

These patients should be treated with a combination of measures, including lifestyle modification and pharmacologic therapy, to a target BP of <140/90 mm Hg. Randomized controlled trials (RCTs) have shown benefits with this target in terms of a reduction in the incidence of coronary heart disease (CHD) events, stroke, and diabetic kidney disease.^10,11

A 2012 meta-analysis of randomized trials involving adults with type 2 diabetes mellitus (T2DM) and comparing intensive BP targets (≤130 mm Hg SBP and ≤80 mm Hg DBP) with standard targets (≤140-160 mm Hg SBP and ≤85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MIs associated with more intense BP control. There was a statistically significant 35% relative risk (RR) reduction in stroke with intensive targets, but lower BP was also associated with an increased risk of hypotension and syncope.¹²

A new lifestyle recommendation in this year’s ADA Standards states that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity.

The 2010 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹³ which randomized 5518 patients with T2DM at high risk for ASCVD to either a target SBP of <120 mm Hg or 130 to 140 mm Hg, found that the patients with the lower SBP target did not benefit in the primary end point (a composite of nonfatal MI, nonfatal stroke, and CV death), but did benefit from nominally significant lower rates of total stroke and nonfatal stroke.

Based on these data, the ADA Standards of Care suggest that, “more intensive BP control may be reasonable in certain motivated, ACCORD-like patients (40-79 years of age with prior evidence of CVD or multiple CV risk factors) who have been educated about the added treatment burden, side effects, and costs of more intensive BP control and for patients who prefer to lower their risk of stroke beyond what can be achieved with usual care.”

Another major study, the 2015 Systolic Blood Pressure Intervention Trial (SPRINT) trial,¹⁴ demonstrated that treating patients with hypertension to a target SBP <120 mm Hg compared to the usual target of <140 mm Hg resulted in a 25% lower RR of the primary outcome (a composite of MI, other acute coronary syndromes, stroke, heart failure, or death from CV causes) and about a 25% reduction in all-cause mortality; however, people with diabetes were not included in the trial, so the applicability of the results to decisions about BP management in patients with diabetes is not known.

In people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.

A 2015 systematic review and meta-analysis of over 100,000 participants looked at SBP lowering in adults with T2DM and found that each 10-mm Hg reduction in SBP was associated with a significantly lower risk of morbidity, CV events, CHD, stroke, albuminuria, and retinopathy.¹⁰ When trials were stratified by mean baseline SBP (<140 mm Hg or ≥140 mm Hg), RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline SBP.

The latest ADA Standards of Care recommend that a lower BP target of 130/80 mm Hg may be appropriate for patients at high risk of CVD if this target can be achieved without undue treatment burden. A DBP of <80 mm Hg may also be appropriate in certain patients including those with a long life expectancy, CKD, elevated urinary albumin excretion, and those with evidence of CVD or associated risk factors.¹⁵ Of note, treating older adults with diabetes to an SBP target of <130 mm Hg has not been shown to improve cardiovascular outcomes,¹⁶ and treating to a diastolic target of <70 mm Hg has been associated with a greater risk of mortality.¹⁷

What are the current recommended treatment options?

Treatment for hypertension in adults with diabetes without albuminuria should include any of the classes of medications demonstrated to reduce CV events in patients with diabetes, such as:

• angiotensin-converting enzyme (ACE) inhibitors,
• angiotensin receptor blockers (ARBs),
• thiazide-like diuretics, and
• dihydropyridine calcium channel blockers.

These recommendations are based on evidence suggesting the lack of superiority of ACE inhibitors and ARBs over other classes of antihypertensive agents for the prevention of CV outcomes in all patients with diabetes.¹⁸ However, in people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.^19-24 Thus, ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and urine albumin/creatinine ratios ≥30 mg/g, as these medications are associated with a reduction in the rate of kidney disease progression.

The use of both an ACE inhibitor and an ARB in combination is not recommended.^25,26 For patients treated with ACE inhibitors, ARBs, or diuretics, serum creatinine/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored.

What are the recommended lifestyle modifications for patients with diabetes and hypertension?

Regular exercise and healthy eating are recommended for all people with diabetes to optimize glycemic control and lose weight (if they are overweight or obese). For patients with hypertension, the DASH diet (available at: https://www.nhlbi.nih.gov/health/health-topics/topics/dash/) is effective at lowering BP. The DASH diet emphasizes reducing sodium intake, increasing potassium intake, limiting alcohol intake, and increasing physical activity. Specifically, sodium intake should be restricted to <2300 mg/d and patients should consume approximately 8 to 10 servings of fruits and vegetables per day and 2 to 3 servings of low-fat dairy per day. Alcohol should be limited to 2 drinks per day for men and one drink per day for women.

People with diabetes who have hypertension should be treated with lifestyle modification and pharmacologic therapy to a target blood pressure of <140/90 mm Hg.

Most adults with diabetes should perform 150 minutes per week of moderate to vigorous exercise, spread over at least 3 days/week. In addition, it is recommended that resistance exercises be performed at least 2 to 3 days/week. Prolonged inactivity is detrimental to health and should be interrupted with activity every 30 minutes.²⁷

Finally, as a part of lifestyle management for all patients with diabetes, smoking cessation is important, as is attention to stress, depression, and anxiety.

Is there an advantage to nighttime dosing of antihypertensive medications?

Yes. Growing evidence suggests that there is an ASCVD benefit to avoiding nocturnal BP dipping. A 2011 RCT of 448 participants with T2DM and hypertension showed a decrease in CV events and mortality during 5.4 years of follow-up if at least one antihypertensive medication was taken at bedtime.²⁸ As a result of this and other evidence,²⁹ consider administering one or more antihypertensive medications at bedtime, although this is not a formal recommendation in the ADA Standards of Care.

Are there any additional issues to be aware of when treating patients with diabetes and hypertension?

Yes. Sometimes patients who have had diabetes for many years have significant orthostatic hypotension secondary to autonomic neuropathy. Postural changes in BP and pulse may require adjustment of BP targets. Home BP self-monitoring and 24-hour ambulatory BP monitoring may indicate white-coat or masked hypertension.

Lipid management

What is the current evidence for lipid treatment in diabetes?

Lipid abnormalities are common in people with diabetes and contribute to the overall high risk of ASCVD in these patients. Subgroup analyses of patients in large trials with diabetes³⁰ and trials involving patients with diabetes³¹ have shown significant improvements in primary and secondary prevention of ASCVD with statin use. A 2008 meta-analysis of 18,686 people with diabetes showed a 9% reduction in all-cause mortality and a 13% reduction in vascular mortality for each 39-mg/dL reduction in low-density lipoprotein (LDL) cholesterol.³² Absolute reductions in mortality are greatest in those with highest risk, but the benefits of statin therapy are clear for low- and moderate-risk individuals with diabetes, too.^33,34 As a result, statins are the medications of choice for lipid lowering and CV risk reduction and should be used in addition to lifestyle management.

Who should get a statin, and how do I choose the optimum dosage?

Patients ages 40 to 75 years with diabetes but without additional ASCVD risk factors should receive a moderate-intensity statin, according to the ADA (see TABLES 1² and 2²). For those with additional CV risk factors, a high-intensity statin should be considered. The American College of Cardiology/American Heart Association ASCVD risk calculator (available at: http://www.cvriskcalculator.com/) may be useful for some patients, but generally, risk is already known to be high for most patients with diabetes. For patients of all ages with diabetes and established ASCVD, high-intensity statin therapy should be added to lifestyle modifications.^35-37

For patients with diabetes who are <40 years with additional ASCVD risk factors, few clinical trial data exist; nevertheless, consider a moderate- or high-intensity statin and lifestyle therapy. Similarly, for patients >75 years who have diabetes and no additional ASCVD risk factors, consider a moderate-intensity statin and lifestyle modifications. For older adults with additional ASCVD risk factors, consider high-intensity statin therapy.^35-37

Statins and cognition. It should be noted that published data have not demonstrated an adverse effect of statins on cognition.³⁸ Statins, however, have been linked to an increased risk of developing diabetes,^39,40 although the absolute increase in risk is small, and much smaller than the benefit derived from preventing the development of coronary disease.

Should total cholesterol and LDL levels be used as targets with statin treatment?

No. Statin doses have primarily been tested against placebo in clinical trials, rather than testing to specific target LDL levels, suggesting that the initiation and intensification of statin therapy be based on a patient’s risk profile.³⁵ When maximally tolerated doses of statins do not lower LDL cholesterol by more than 30% from the patient’s baseline, there is currently no good evidence that combination therapy would be helpful, so regular monitoring of lipid levels has limited value. A lipid profile that includes levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides should be obtained at initial medical evaluation, at diagnosis of diabetes, and every 5 years thereafter or before the initiation of statin therapy. Ongoing testing may be appropriate in individual circumstances and to monitor for adherence to, or efficacy of, therapy.

What should I do for my patients who can’t tolerate statins?

Try a lower dose or a different statin before eliminating the class. Research has shown that even small doses (eg, rosuvastatin 5 mg) have some benefit.⁴¹

How do combination treatments figure into the current treatment of lipids in patients with diabetes?

It depends on the agent and the patient’s profile.

Fenofibrate. The ADA does not recommend automatically adding fenofibrate to statin therapy because the combination is associated with increased risks for abnormal transaminase levels, myositis, and rhabdomyolysis. In the ACCORD trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, nonfatal MIs, or nonfatal strokes compared with simvastatin alone.⁴²

Recommend statin therapy to all patients with diabetes over age 40; use a moderate- or high-intensity agent depending upon the degree of cardiac risk.

That said, a subgroup analysis suggested a benefit for men with both a triglyceride level ≥204 mg/dL (2.3 mmol/L) and an HDL cholesterol level ≤34 mg/dL (0.9 mmol/L).⁴² For this reason, the combination of a statin and fenofibrate may be considered for men who meet these laboratory parameters. In addition, consider medical therapy for triglyceride levels ≥500 mg/dL to reduce the risk of pancreatitis.

Ezetimibe. Recommendations regarding ezetimibe are based on the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), a 2015 RCT including over 18,000 patients that compared treatment with ezetimibe and simvastatin to simvastatin alone.⁴³ Individuals in the trial were ≥50 years of age and had experienced an ACS within the preceding 10 days. In those with diabetes, the combination of moderate-intensity simvastatin (40 mg) and ezetimibe (10 mg) significantly reduced major adverse CV events with an absolute risk reduction of 5% (40% vs 45%) and an RR reduction of 14% over moderate-intensity simvastatin (40 mg) alone.

Based on these results, patients with diabetes and a recent ACS should be considered for combination therapy with ezetimibe and a moderate-intensity statin. The combination should also be considered in patients with diabetes and a history of ASCVD who cannot tolerate high-intensity statins.⁴³

Recommend daily aspirin therapy to patients ages ≥50 years who have diabetes and at least one additional cardiovascular risk factor, but no bleeding risk.

Niacin. The ADA currently does not recommend niacin in combination with a statin because of lack of efficacy on major ASCVD outcomes, possible increased risk of ischemic stroke, and adverse effects.⁴⁴

What are the recommendations for the use of PCSK-9 inhibitors?

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors (ie, evolucumab and alirocumab) may be considered as adjunctive therapy to statins for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol. They may also be considered for those in whom high-intensity statin therapy is indicated, but not tolerated.

Antiplatelet agents

Who should take aspirin for primary prevention of CVD?

Both women and men ages ≥50 years who have diabetes and at least one additional CV risk factor (family history of premature ASCVD, hypertension, tobacco use, dyslipidemia, or albuminuria) should consider taking daily aspirin therapy (75-162 mg/d) if they do not have an excessive bleeding risk.^45,46 The most common dose in the United States is 81 mg. This recommendation is supported by a 2010 consensus statement of the American Diabetes Association, American Heart Association, and the American College of Cardiology.⁴⁷

Should patients with diabetes and heart disease receive antiplatelet therapy?

Yes. The evidence is clear that people with known diabetes and ASCVD benefit from aspirin therapy, according to the 2017 Standards of Care. Clopidogrel 75 mg/d is an appropriate alternative for patients who are allergic to aspirin. Dual antiplatelet therapy (a P2Y12 receptor antagonist and aspirin) should be used for as long as one year after an ACS and may have benefits beyond this period.⁴⁸

Established heart disease

Are there specific recommendations for patients with diabetes and CHD?

According to the ADA Standards, there is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used. In addition, consider ACE inhibitors to reduce the future risk of CV events. In patients with a prior MI, continue beta-blocker therapy for at least 2 years post event.⁴⁹

Which medications should I avoid, or approach with caution, in patients with congestive heart failure (CHF)?

Thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, and metformin all require careful attention. This is especially important to know when you consider that almost half of all patients with T2DM will develop heart failure.⁵⁰

Thiazolidinediones. The 2017 Standards of Care state that patients with diabetes and symptomatic congestive heart failure should not receive thiazolidinediones, as they can worsen heart failure status via fluid retention. As such, they are contraindicated in patients with class III and IV heart failure.⁵¹

DPP-4 inhibitors. The studies on DPP-4 inhibitors and heart failure have had mixed results. The 2013 SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction) 53 trial⁵² showed that patients treated with saxagliptin were more likely to be hospitalized for heart failure than those taking placebo (3.5% vs 2.8%, respectively). However, the 2015 EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care)⁵³ trial and the 2015 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)⁵⁴ trial evaluated heart failure and mortality outcomes in patients with alogliptin and sitagliptin, respectively, compared to placebo, and did not show a relationship to heart failure.

Metformin may be used in people who have T2DM and stable CHF if their eGFR remains >30 mL/min; it should be withheld from patients with unstable heart failure and those who are hospitalized with CHF.

Are there antihyperglycemic medications that reduce CV morbidity and mortality in those with established ASCVD?

Yes. This year’s ADA Standards indicate that certain glucose-lowering medications—specifically empagliflozin (a sodium–glucose cotransporter [SGLT]-2 inhibitor) and liraglutide (a glucagon-like peptide [GLP]-1 receptor agonist)—have been shown to be beneficial for those with established CVD. According to the 2017 Standards of Care, “In patients with longstanding suboptimally controlled T2DM and established ASCVD, empagliflozin or liraglutide should be considered, as they have been shown to reduce CV and all-cause mortality when added to standard care.”² The studies that provide support for their use are summarized below. Ongoing studies are investigating the CV effects of other agents in these drug classes.

There is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used.

Empagliflozin. The 2015 EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study⁵⁵ was a randomized double-blind study of empagliflozin vs placebo and usual care in patients with diabetes and established CVD. Over a median follow-up of 3.1 years, treatment with empagliflozin reduced the aggregate outcome of MI, stroke, and CV death by 14%, reduced CV deaths by 38%, and decreased deaths from any cause by 32%. In December 2016, the FDA announced a new indication for empagliflozin: to reduce the risk of CV death in adult patients with T2DM and CVD.⁵⁶

Liraglutide. The LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results: A Long Term Evaluation) trial⁵⁷ was a double-blind randomized trial of liraglutide vs placebo added to usual care in patients with T2DM at high risk for CVD or with existing CVD. More than 80% of the participants had existing CVD including a history of prior MI, cerebrovascular disease, or peripheral vascular disease. After a median follow-up of 3.8 years, the group taking liraglutide demonstrated a 13% reduction in the composite outcome of MI, stroke, or CV death, a 22% reduction in CV death, and a 15% reduction in death from any cause, compared with placebo.⁵⁷

CORRESPONDENCE
Neil Skolnik, MD, Abington-Jefferson Health, 500 Old York Rd, Ste 108, Jenkintown, PA 19046; [email protected].

The authors thank Sarah Bradley, director, professional engagement & collaboration at the American Diabetes Association, for her editorial and organizational assistance in the preparation of this manuscript.

More than 29 million Americans have diabetes, and each year another 1.7 million are given the diagnosis.¹ Prediabetes is even more common; over one-third of US adults ages 20 years and older, and more than half of those who are ages 65 and older, have attained this precursor status, representing another 86 million Americans.¹

Because the evidence base for the management of diabetes is rapidly expanding, the American Diabetes Association’s (ADA) Professional Practice Committee updates its Standards of Medical Care in Diabetes annually to incorporate new evidence into its recommendations. The 2017 Standards of Care are available at: professional.diabetes.org/jfp.²

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality for people with diabetes, and is the largest contributor to the direct and indirect costs of the disease.² As a result, all patients with diabetes should have cardiovascular (CV) risk factors, including dyslipidemia, hypertension, smoking, a family history of premature coronary disease, and the presence of albuminuria, assessed at least annually.² Numerous studies have demonstrated the efficacy of controlling individual CV risk factors in preventing or slowing ASCVD in people with diabetes. Even larger benefits, including reduced ASCVD morbidity and mortality, can be achieved when multiple risk factors are addressed simultaneously.³

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for the 29 million Americans with diabetes, and is the largest contributor to the direct and indirect costs of diabetes.

To hone your management of CV risks in patients with diabetes, we’ve put together this Q&A pointing out the elements of the ADA’s 2017 Standards of Care that are most relevant to the management of patients at risk for, or with established, ASCVD.

Screening

Since ASCVD so commonly co-occurs with diabetes, should I routinely screen asymptomatic patients with diabetes for heart disease?

No. The current evidence suggests that outcomes are NOT improved by screening people before they develop symptoms of ASCVD,⁴ and widespread ASCVD screening has not been shown to be cost-effective. Cardiac testing should be reserved for those with typical or atypical symptoms or those with an abnormal resting electrocardiogram (EKG).

Lifestyle modification

What are the benefits of lifestyle interventions?

The benefits include not only lost pounds, but improved mobility, physical and sexual functioning, and health-related quality of life. Recommend that all overweight patients with diabetes take advantage of intensive lifestyle interventions focusing on weight loss through decreased caloric intake and increased physical activity as per the Look AHEAD (Action for Health in Diabetes) trial.⁵ Although the intensive lifestyle intervention in the Look AHEAD trial did not decrease CV outcomes over 10 years of follow-up, it did improve control of CV risk factors and led to people in the intervention group taking fewer glucose-, blood pressure (BP)-, and lipid-lowering medications than those in the standard care group.

There is no one diet that is recommended for all people with diabetes. Weight reduction often requires intensive intervention. In order for weight loss diets to be sustainable, they must include patient preferences.

People with diabetes should be encouraged to receive individualized medical nutrition therapy (MNT), preferably from a registered dietitian who is well versed in nutritional management for diabetes. Such MNT is associated with a 0.5% to 2% decrease in A1c levels for people with type 2 diabetes.^6-9 Specific healthy diets include the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and plant-based diets.

A new lifestyle recommendation in this year’s ADA Standards is that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity. This appears to have glycemic benefits.²

Hypertension/BP management

When should I initiate hypertension treatment in patients with diabetes?

Nonpharmacologic therapy is reasonable in people with diabetes and mildly elevated BP (>120/80 mm Hg). If systolic blood pressure (SBP) is confirmed to be >140 mm Hg and/or diastolic blood pressure (DBP) is confirmed to be >90 mm Hg, the ADA recommends initiating pharmacologic therapy along with nonpharmacologic strategies. For patients with confirmed office-based BP >160/100 mm Hg, the ADA advises initiating lifestyle modifications as well as 2 pharmacologic medications (or a single pill combination of agents).²

What is the recommended BP target for patients with diabetes and hypertension?

These patients should be treated with a combination of measures, including lifestyle modification and pharmacologic therapy, to a target BP of <140/90 mm Hg. Randomized controlled trials (RCTs) have shown benefits with this target in terms of a reduction in the incidence of coronary heart disease (CHD) events, stroke, and diabetic kidney disease.^10,11

A 2012 meta-analysis of randomized trials involving adults with type 2 diabetes mellitus (T2DM) and comparing intensive BP targets (≤130 mm Hg SBP and ≤80 mm Hg DBP) with standard targets (≤140-160 mm Hg SBP and ≤85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MIs associated with more intense BP control. There was a statistically significant 35% relative risk (RR) reduction in stroke with intensive targets, but lower BP was also associated with an increased risk of hypotension and syncope.¹²

A new lifestyle recommendation in this year’s ADA Standards states that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity.

The 2010 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹³ which randomized 5518 patients with T2DM at high risk for ASCVD to either a target SBP of <120 mm Hg or 130 to 140 mm Hg, found that the patients with the lower SBP target did not benefit in the primary end point (a composite of nonfatal MI, nonfatal stroke, and CV death), but did benefit from nominally significant lower rates of total stroke and nonfatal stroke.

Based on these data, the ADA Standards of Care suggest that, “more intensive BP control may be reasonable in certain motivated, ACCORD-like patients (40-79 years of age with prior evidence of CVD or multiple CV risk factors) who have been educated about the added treatment burden, side effects, and costs of more intensive BP control and for patients who prefer to lower their risk of stroke beyond what can be achieved with usual care.”

Another major study, the 2015 Systolic Blood Pressure Intervention Trial (SPRINT) trial,¹⁴ demonstrated that treating patients with hypertension to a target SBP <120 mm Hg compared to the usual target of <140 mm Hg resulted in a 25% lower RR of the primary outcome (a composite of MI, other acute coronary syndromes, stroke, heart failure, or death from CV causes) and about a 25% reduction in all-cause mortality; however, people with diabetes were not included in the trial, so the applicability of the results to decisions about BP management in patients with diabetes is not known.

In people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.

A 2015 systematic review and meta-analysis of over 100,000 participants looked at SBP lowering in adults with T2DM and found that each 10-mm Hg reduction in SBP was associated with a significantly lower risk of morbidity, CV events, CHD, stroke, albuminuria, and retinopathy.¹⁰ When trials were stratified by mean baseline SBP (<140 mm Hg or ≥140 mm Hg), RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline SBP.

The latest ADA Standards of Care recommend that a lower BP target of 130/80 mm Hg may be appropriate for patients at high risk of CVD if this target can be achieved without undue treatment burden. A DBP of <80 mm Hg may also be appropriate in certain patients including those with a long life expectancy, CKD, elevated urinary albumin excretion, and those with evidence of CVD or associated risk factors.¹⁵ Of note, treating older adults with diabetes to an SBP target of <130 mm Hg has not been shown to improve cardiovascular outcomes,¹⁶ and treating to a diastolic target of <70 mm Hg has been associated with a greater risk of mortality.¹⁷

What are the current recommended treatment options?

Treatment for hypertension in adults with diabetes without albuminuria should include any of the classes of medications demonstrated to reduce CV events in patients with diabetes, such as:

• angiotensin-converting enzyme (ACE) inhibitors,
• angiotensin receptor blockers (ARBs),
• thiazide-like diuretics, and
• dihydropyridine calcium channel blockers.

These recommendations are based on evidence suggesting the lack of superiority of ACE inhibitors and ARBs over other classes of antihypertensive agents for the prevention of CV outcomes in all patients with diabetes.¹⁸ However, in people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.^19-24 Thus, ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and urine albumin/creatinine ratios ≥30 mg/g, as these medications are associated with a reduction in the rate of kidney disease progression.

The use of both an ACE inhibitor and an ARB in combination is not recommended.^25,26 For patients treated with ACE inhibitors, ARBs, or diuretics, serum creatinine/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored.

What are the recommended lifestyle modifications for patients with diabetes and hypertension?

Regular exercise and healthy eating are recommended for all people with diabetes to optimize glycemic control and lose weight (if they are overweight or obese). For patients with hypertension, the DASH diet (available at: https://www.nhlbi.nih.gov/health/health-topics/topics/dash/) is effective at lowering BP. The DASH diet emphasizes reducing sodium intake, increasing potassium intake, limiting alcohol intake, and increasing physical activity. Specifically, sodium intake should be restricted to <2300 mg/d and patients should consume approximately 8 to 10 servings of fruits and vegetables per day and 2 to 3 servings of low-fat dairy per day. Alcohol should be limited to 2 drinks per day for men and one drink per day for women.

People with diabetes who have hypertension should be treated with lifestyle modification and pharmacologic therapy to a target blood pressure of <140/90 mm Hg.

Most adults with diabetes should perform 150 minutes per week of moderate to vigorous exercise, spread over at least 3 days/week. In addition, it is recommended that resistance exercises be performed at least 2 to 3 days/week. Prolonged inactivity is detrimental to health and should be interrupted with activity every 30 minutes.²⁷

Finally, as a part of lifestyle management for all patients with diabetes, smoking cessation is important, as is attention to stress, depression, and anxiety.

Is there an advantage to nighttime dosing of antihypertensive medications?

Yes. Growing evidence suggests that there is an ASCVD benefit to avoiding nocturnal BP dipping. A 2011 RCT of 448 participants with T2DM and hypertension showed a decrease in CV events and mortality during 5.4 years of follow-up if at least one antihypertensive medication was taken at bedtime.²⁸ As a result of this and other evidence,²⁹ consider administering one or more antihypertensive medications at bedtime, although this is not a formal recommendation in the ADA Standards of Care.

Are there any additional issues to be aware of when treating patients with diabetes and hypertension?

Yes. Sometimes patients who have had diabetes for many years have significant orthostatic hypotension secondary to autonomic neuropathy. Postural changes in BP and pulse may require adjustment of BP targets. Home BP self-monitoring and 24-hour ambulatory BP monitoring may indicate white-coat or masked hypertension.

Lipid management

What is the current evidence for lipid treatment in diabetes?

Lipid abnormalities are common in people with diabetes and contribute to the overall high risk of ASCVD in these patients. Subgroup analyses of patients in large trials with diabetes³⁰ and trials involving patients with diabetes³¹ have shown significant improvements in primary and secondary prevention of ASCVD with statin use. A 2008 meta-analysis of 18,686 people with diabetes showed a 9% reduction in all-cause mortality and a 13% reduction in vascular mortality for each 39-mg/dL reduction in low-density lipoprotein (LDL) cholesterol.³² Absolute reductions in mortality are greatest in those with highest risk, but the benefits of statin therapy are clear for low- and moderate-risk individuals with diabetes, too.^33,34 As a result, statins are the medications of choice for lipid lowering and CV risk reduction and should be used in addition to lifestyle management.

Who should get a statin, and how do I choose the optimum dosage?

Patients ages 40 to 75 years with diabetes but without additional ASCVD risk factors should receive a moderate-intensity statin, according to the ADA (see TABLES 1² and 2²). For those with additional CV risk factors, a high-intensity statin should be considered. The American College of Cardiology/American Heart Association ASCVD risk calculator (available at: http://www.cvriskcalculator.com/) may be useful for some patients, but generally, risk is already known to be high for most patients with diabetes. For patients of all ages with diabetes and established ASCVD, high-intensity statin therapy should be added to lifestyle modifications.^35-37

For patients with diabetes who are <40 years with additional ASCVD risk factors, few clinical trial data exist; nevertheless, consider a moderate- or high-intensity statin and lifestyle therapy. Similarly, for patients >75 years who have diabetes and no additional ASCVD risk factors, consider a moderate-intensity statin and lifestyle modifications. For older adults with additional ASCVD risk factors, consider high-intensity statin therapy.^35-37

Statins and cognition. It should be noted that published data have not demonstrated an adverse effect of statins on cognition.³⁸ Statins, however, have been linked to an increased risk of developing diabetes,^39,40 although the absolute increase in risk is small, and much smaller than the benefit derived from preventing the development of coronary disease.

Should total cholesterol and LDL levels be used as targets with statin treatment?

No. Statin doses have primarily been tested against placebo in clinical trials, rather than testing to specific target LDL levels, suggesting that the initiation and intensification of statin therapy be based on a patient’s risk profile.³⁵ When maximally tolerated doses of statins do not lower LDL cholesterol by more than 30% from the patient’s baseline, there is currently no good evidence that combination therapy would be helpful, so regular monitoring of lipid levels has limited value. A lipid profile that includes levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides should be obtained at initial medical evaluation, at diagnosis of diabetes, and every 5 years thereafter or before the initiation of statin therapy. Ongoing testing may be appropriate in individual circumstances and to monitor for adherence to, or efficacy of, therapy.

What should I do for my patients who can’t tolerate statins?

Try a lower dose or a different statin before eliminating the class. Research has shown that even small doses (eg, rosuvastatin 5 mg) have some benefit.⁴¹

How do combination treatments figure into the current treatment of lipids in patients with diabetes?

It depends on the agent and the patient’s profile.

Fenofibrate. The ADA does not recommend automatically adding fenofibrate to statin therapy because the combination is associated with increased risks for abnormal transaminase levels, myositis, and rhabdomyolysis. In the ACCORD trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, nonfatal MIs, or nonfatal strokes compared with simvastatin alone.⁴²

Recommend statin therapy to all patients with diabetes over age 40; use a moderate- or high-intensity agent depending upon the degree of cardiac risk.

That said, a subgroup analysis suggested a benefit for men with both a triglyceride level ≥204 mg/dL (2.3 mmol/L) and an HDL cholesterol level ≤34 mg/dL (0.9 mmol/L).⁴² For this reason, the combination of a statin and fenofibrate may be considered for men who meet these laboratory parameters. In addition, consider medical therapy for triglyceride levels ≥500 mg/dL to reduce the risk of pancreatitis.

Ezetimibe. Recommendations regarding ezetimibe are based on the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), a 2015 RCT including over 18,000 patients that compared treatment with ezetimibe and simvastatin to simvastatin alone.⁴³ Individuals in the trial were ≥50 years of age and had experienced an ACS within the preceding 10 days. In those with diabetes, the combination of moderate-intensity simvastatin (40 mg) and ezetimibe (10 mg) significantly reduced major adverse CV events with an absolute risk reduction of 5% (40% vs 45%) and an RR reduction of 14% over moderate-intensity simvastatin (40 mg) alone.

Based on these results, patients with diabetes and a recent ACS should be considered for combination therapy with ezetimibe and a moderate-intensity statin. The combination should also be considered in patients with diabetes and a history of ASCVD who cannot tolerate high-intensity statins.⁴³

Recommend daily aspirin therapy to patients ages ≥50 years who have diabetes and at least one additional cardiovascular risk factor, but no bleeding risk.

Niacin. The ADA currently does not recommend niacin in combination with a statin because of lack of efficacy on major ASCVD outcomes, possible increased risk of ischemic stroke, and adverse effects.⁴⁴

What are the recommendations for the use of PCSK-9 inhibitors?

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors (ie, evolucumab and alirocumab) may be considered as adjunctive therapy to statins for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol. They may also be considered for those in whom high-intensity statin therapy is indicated, but not tolerated.

Antiplatelet agents

Who should take aspirin for primary prevention of CVD?

Both women and men ages ≥50 years who have diabetes and at least one additional CV risk factor (family history of premature ASCVD, hypertension, tobacco use, dyslipidemia, or albuminuria) should consider taking daily aspirin therapy (75-162 mg/d) if they do not have an excessive bleeding risk.^45,46 The most common dose in the United States is 81 mg. This recommendation is supported by a 2010 consensus statement of the American Diabetes Association, American Heart Association, and the American College of Cardiology.⁴⁷

Should patients with diabetes and heart disease receive antiplatelet therapy?

Yes. The evidence is clear that people with known diabetes and ASCVD benefit from aspirin therapy, according to the 2017 Standards of Care. Clopidogrel 75 mg/d is an appropriate alternative for patients who are allergic to aspirin. Dual antiplatelet therapy (a P2Y12 receptor antagonist and aspirin) should be used for as long as one year after an ACS and may have benefits beyond this period.⁴⁸

Established heart disease

Are there specific recommendations for patients with diabetes and CHD?

According to the ADA Standards, there is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used. In addition, consider ACE inhibitors to reduce the future risk of CV events. In patients with a prior MI, continue beta-blocker therapy for at least 2 years post event.⁴⁹

Which medications should I avoid, or approach with caution, in patients with congestive heart failure (CHF)?

Thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, and metformin all require careful attention. This is especially important to know when you consider that almost half of all patients with T2DM will develop heart failure.⁵⁰

Thiazolidinediones. The 2017 Standards of Care state that patients with diabetes and symptomatic congestive heart failure should not receive thiazolidinediones, as they can worsen heart failure status via fluid retention. As such, they are contraindicated in patients with class III and IV heart failure.⁵¹

DPP-4 inhibitors. The studies on DPP-4 inhibitors and heart failure have had mixed results. The 2013 SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction) 53 trial⁵² showed that patients treated with saxagliptin were more likely to be hospitalized for heart failure than those taking placebo (3.5% vs 2.8%, respectively). However, the 2015 EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care)⁵³ trial and the 2015 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)⁵⁴ trial evaluated heart failure and mortality outcomes in patients with alogliptin and sitagliptin, respectively, compared to placebo, and did not show a relationship to heart failure.

Metformin may be used in people who have T2DM and stable CHF if their eGFR remains >30 mL/min; it should be withheld from patients with unstable heart failure and those who are hospitalized with CHF.

Are there antihyperglycemic medications that reduce CV morbidity and mortality in those with established ASCVD?

Yes. This year’s ADA Standards indicate that certain glucose-lowering medications—specifically empagliflozin (a sodium–glucose cotransporter [SGLT]-2 inhibitor) and liraglutide (a glucagon-like peptide [GLP]-1 receptor agonist)—have been shown to be beneficial for those with established CVD. According to the 2017 Standards of Care, “In patients with longstanding suboptimally controlled T2DM and established ASCVD, empagliflozin or liraglutide should be considered, as they have been shown to reduce CV and all-cause mortality when added to standard care.”² The studies that provide support for their use are summarized below. Ongoing studies are investigating the CV effects of other agents in these drug classes.

There is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used.

Empagliflozin. The 2015 EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study⁵⁵ was a randomized double-blind study of empagliflozin vs placebo and usual care in patients with diabetes and established CVD. Over a median follow-up of 3.1 years, treatment with empagliflozin reduced the aggregate outcome of MI, stroke, and CV death by 14%, reduced CV deaths by 38%, and decreased deaths from any cause by 32%. In December 2016, the FDA announced a new indication for empagliflozin: to reduce the risk of CV death in adult patients with T2DM and CVD.⁵⁶

Liraglutide. The LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results: A Long Term Evaluation) trial⁵⁷ was a double-blind randomized trial of liraglutide vs placebo added to usual care in patients with T2DM at high risk for CVD or with existing CVD. More than 80% of the participants had existing CVD including a history of prior MI, cerebrovascular disease, or peripheral vascular disease. After a median follow-up of 3.8 years, the group taking liraglutide demonstrated a 13% reduction in the composite outcome of MI, stroke, or CV death, a 22% reduction in CV death, and a 15% reduction in death from any cause, compared with placebo.⁵⁷

CORRESPONDENCE
Neil Skolnik, MD, Abington-Jefferson Health, 500 Old York Rd, Ste 108, Jenkintown, PA 19046; [email protected].

The authors thank Sarah Bradley, director, professional engagement & collaboration at the American Diabetes Association, for her editorial and organizational assistance in the preparation of this manuscript.

Photo courtesy of Novartis

The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).

The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).

Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.

The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.

Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.

Midostaurin in AML

The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).

The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.

Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Photo courtesy of Novartis

The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).

The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).

Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.

The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.

Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.

Midostaurin in AML

The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).

The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.

Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Photo courtesy of Novartis

The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).

The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).

Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.

The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.

Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.

Midostaurin in AML

The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).

The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.

Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.

The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.

The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).

It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).

The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.

The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.

Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.

Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.

The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.

The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).

It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).

The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.

The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.

Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.

Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.

The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.

The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).

It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).

The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.

The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.

Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.

Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.² An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).² Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).² However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.⁵

[polldaddy:9724288]

STUDY SUMMARY

Melatonin tops amitriptyline in >50% improvement in headache frequency

This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.¹ Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.

The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).

WHAT’S NEW

An effective migraine prevention alternative with minimal adverse effects

Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.² An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).² Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).² However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.⁵

[polldaddy:9724288]

STUDY SUMMARY

Melatonin tops amitriptyline in >50% improvement in headache frequency

This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.¹ Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.

The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).

WHAT’S NEW

An effective migraine prevention alternative with minimal adverse effects

Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.² An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).² Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).² However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.⁵

[polldaddy:9724288]

STUDY SUMMARY

Melatonin tops amitriptyline in >50% improvement in headache frequency

This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.¹ Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.

The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).

WHAT’S NEW

An effective migraine prevention alternative with minimal adverse effects

Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

A 34-year-old woman came to our clinic because she was concerned about her thumbnail, which had turned green. Although her finger didn’t hurt, she was bothered by its appearance. Several months earlier, the woman had sought care at a different clinic because the same nail had become brittle and come loose from the nail bed, which was spongy. The physician advised her that she had onychomycosis and prescribed ciclopirox lacquer, but it didn’t help.

Over the next 3 weeks, she noticed a faint green hue developing at the tip of the nail, which expanded and intensified in color (FIGURE). The patient was a mother who worked at home, washed dishes by hand daily, and bathed her children. Her past medical history was significant for type 1 diabetes mellitus and Hashimoto’s thyroiditis. She had no other symptoms.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Green nail syndrome caused by Pseudomonas aeruginosa

This patient had green nail syndrome (GNS), an infection of the nail bed caused by Pseudomonas aeruginosa. These bacteria produce pyocyanin, a blue-green pigment that discolors the nail.¹ GNS often occurs in patients with prior nail problems, such as onychomycosis, onycholysis, trauma, chronic paronychia, or psoriasis.

Nail disease disrupts the integumentary barrier and allows a portal of entry for bacteria. Scanning electron microscopy of patients with GNS has shown that fungal infections create tunnel-like structures in the nail keratin, and P aeruginosa grows in these spaces.² Nails with prior nail disease that are chronically exposed to moisture are at greatest risk of developing GNS,^3,4 and it is typical for only one nail to be involved.⁵Pseudomonas is the most common bacterial infection of the nails, but is not well known because it is rarely reported and patients often don’t seek care.⁶

Pseudomonas is the most common bacterial infection of the nails, but is not well known because it is rarely reported and patients often don't seek care.

In our patient’s case, her prior onychomycosis helped to create a favorable environment for the growth of the bacteria. Onycholysis—characterized by separation of the nail plate from the nail bed—was also present in our patient, based on her description of a “spongy” nail bed and loose nail, allowing moisture and bacteria to infiltrate the space. Onycholysis is associated with hypothyroidism, which the patient also had.⁷ The frequent soaking of her hands during dishwashing and bathing her children helped to provide the moist environment in which Pseudomonas thrives.

As was the case in this patient, GNS is often painless, or may be accompanied by mild tenderness of the nail. Patients may seek treatment primarily for cosmetic reasons.

GNS can be diagnosed by clinical observation and characteristic pigmentation along with an appropriate patient history.⁴ Culture of the nail bed may be helpful if bacterial resistance or co-infection with fungal organisms is suspected.

Changes in nail color can be a sign of many conditions

Nail discoloration, or chromonychia, can present in a variety of colors. Nail findings may represent an isolated disease or provide an important clinical clue to other systemic diseases.⁸ The specific shade of discoloration helps to differentiate the underlying pathology.

Yellow nail syndrome. As the name implies, this syndrome typically causes yellow discoloration of the nail (although yellow-green is also possible). Yellow nail syndrome is believed to be due to microvascular permeability, which also accounts for its associated clinical triad: hypoalbuminemia, pleural effusion, and lymphedema. Yellow nail syndrome may be seen in patients with bronchiectasis, internal malignancies, immunodeficiency, and rheumatoid arthritis.⁸

Nail bed hematoma. Among the most common causes of nail discoloration, these lesions typically appear as reddish to reddish-black, depending on the age of the bleed, and will often have streaks at the distal margin of the lesion.⁹ Risk factors for hemorrhage include blood thinners and clotting disorders. Subungual hemorrhages that do not grow out with the nail, or that recur in the same place, may require biopsy.⁹

Subungual melanoma causes black-brown discoloration of the nails, and may form a longitudinal band in the nail.⁹ Longitudinal melanonychia is a common variant in African American individuals.¹⁰ Features that increase the likelihood of melanoma include a family history of melanoma, a sudden change in the appearance of the lesion, band width greater than 3 mm, pigment changes extending into the cuticle (known as Hutchinson’s sign), and nail plate disruption.

Dermoscopy, the technique of using surface microscopy to examine the skin, may be helpful in distinguishing nail lesions. (See a video on how to perform dermoscopy here: http://bit.ly/2pyJ3xN.)

Nonmelanocytic lesions tend to have homogeneously distributed pigment, while melanocytic lesions contain granules of pigment in cellular inclusions. Any suspicion of melanoma warrants a punch biopsy.¹¹

Medication-induced effects. Minocycline may cause bluish nail discoloration similar to that produced by infection with P aeruginosa, but it is rare for only a single nail to be involved. In addition, pigmentation changes are often present elsewhere on the body, including the sclerae, teeth, and pinna.

Another medication known to color the nails blue is colloidal silver, which is still sold as a dietary supplement or homeopathic remedy to treat a wide range of ailments.⁶ (Of note: In 1999, the Food and Drug Administration issued a final rule saying that colloidal silver isn’t safe or effective for treating any disease or condition.¹²)

Glomus tumor. Another cause of blue nails is glomus tumors, relatively uncommon perivascular neoplasms that are typically found in the subungual region. These tumors are generally accompanied by localized tenderness, cold sensitivity, and paroxysms of excruciating pain that are disproportional to the size of the tumor.

Briefly soaking the nail in a bleach solution helps to suppress bacterial growth.

Imaging studies may aid in the diagnosis, in addition to pathologic confirmation. Magnetic resonance imaging is the most sensitive imaging modality; if a glomus tumor is present, it most often appears as a well-circumscribed T2 hyperintense lesion.¹³

Exogenous pigmentation. Nails may become discolored due to exposure to various toxins or chemicals. Frequent culprits include eosin, methylene blue, henna, hair dye, and tobacco.⁹

Antibiotics and measures to keep the nail dry will help resolve infection

When chronic nail wetness is a contributing factor, treatment begins with measures to keep the nails dry. In addition, either topical or systemic antibiotics may be used to eradicate the infection. Topical applications with agents such as nadifloxacin have been shown to be effective in several case reports,³ but large-scale controlled trials are lacking. Fluoroquinolones are regarded as first-line systemic treatment.⁵ Briefly soaking the nail in a diluted sodium hypochlorite (bleach) solution also helps to suppress bacterial growth. Nail extraction may be required in refractory cases.

For our patient, we prescribed ciprofloxacin 500 mg twice a day for 10 days, plus bleach soaks (one part bleach to 4 parts water) twice a day. We recommended that our patient wear gloves for household tasks that involved immersing her hands in water, and drying her finger with a hair dryer after bathing.

CORRESPONDENCE
David Gish, MD, University of Virginia Health System, 1215 Lee St. Charlottesville, VA 22908; [email protected].

A 34-year-old woman came to our clinic because she was concerned about her thumbnail, which had turned green. Although her finger didn’t hurt, she was bothered by its appearance. Several months earlier, the woman had sought care at a different clinic because the same nail had become brittle and come loose from the nail bed, which was spongy. The physician advised her that she had onychomycosis and prescribed ciclopirox lacquer, but it didn’t help.

Over the next 3 weeks, she noticed a faint green hue developing at the tip of the nail, which expanded and intensified in color (FIGURE). The patient was a mother who worked at home, washed dishes by hand daily, and bathed her children. Her past medical history was significant for type 1 diabetes mellitus and Hashimoto’s thyroiditis. She had no other symptoms.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Green nail syndrome caused by Pseudomonas aeruginosa

This patient had green nail syndrome (GNS), an infection of the nail bed caused by Pseudomonas aeruginosa. These bacteria produce pyocyanin, a blue-green pigment that discolors the nail.¹ GNS often occurs in patients with prior nail problems, such as onychomycosis, onycholysis, trauma, chronic paronychia, or psoriasis.

Nail disease disrupts the integumentary barrier and allows a portal of entry for bacteria. Scanning electron microscopy of patients with GNS has shown that fungal infections create tunnel-like structures in the nail keratin, and P aeruginosa grows in these spaces.² Nails with prior nail disease that are chronically exposed to moisture are at greatest risk of developing GNS,^3,4 and it is typical for only one nail to be involved.⁵Pseudomonas is the most common bacterial infection of the nails, but is not well known because it is rarely reported and patients often don’t seek care.⁶

Pseudomonas is the most common bacterial infection of the nails, but is not well known because it is rarely reported and patients often don't seek care.

In our patient’s case, her prior onychomycosis helped to create a favorable environment for the growth of the bacteria. Onycholysis—characterized by separation of the nail plate from the nail bed—was also present in our patient, based on her description of a “spongy” nail bed and loose nail, allowing moisture and bacteria to infiltrate the space. Onycholysis is associated with hypothyroidism, which the patient also had.⁷ The frequent soaking of her hands during dishwashing and bathing her children helped to provide the moist environment in which Pseudomonas thrives.

As was the case in this patient, GNS is often painless, or may be accompanied by mild tenderness of the nail. Patients may seek treatment primarily for cosmetic reasons.

GNS can be diagnosed by clinical observation and characteristic pigmentation along with an appropriate patient history.⁴ Culture of the nail bed may be helpful if bacterial resistance or co-infection with fungal organisms is suspected.

Changes in nail color can be a sign of many conditions

Nail discoloration, or chromonychia, can present in a variety of colors. Nail findings may represent an isolated disease or provide an important clinical clue to other systemic diseases.⁸ The specific shade of discoloration helps to differentiate the underlying pathology.

Yellow nail syndrome. As the name implies, this syndrome typically causes yellow discoloration of the nail (although yellow-green is also possible). Yellow nail syndrome is believed to be due to microvascular permeability, which also accounts for its associated clinical triad: hypoalbuminemia, pleural effusion, and lymphedema. Yellow nail syndrome may be seen in patients with bronchiectasis, internal malignancies, immunodeficiency, and rheumatoid arthritis.⁸

Nail bed hematoma. Among the most common causes of nail discoloration, these lesions typically appear as reddish to reddish-black, depending on the age of the bleed, and will often have streaks at the distal margin of the lesion.⁹ Risk factors for hemorrhage include blood thinners and clotting disorders. Subungual hemorrhages that do not grow out with the nail, or that recur in the same place, may require biopsy.⁹

Subungual melanoma causes black-brown discoloration of the nails, and may form a longitudinal band in the nail.⁹ Longitudinal melanonychia is a common variant in African American individuals.¹⁰ Features that increase the likelihood of melanoma include a family history of melanoma, a sudden change in the appearance of the lesion, band width greater than 3 mm, pigment changes extending into the cuticle (known as Hutchinson’s sign), and nail plate disruption.

Dermoscopy, the technique of using surface microscopy to examine the skin, may be helpful in distinguishing nail lesions. (See a video on how to perform dermoscopy here: http://bit.ly/2pyJ3xN.)

Nonmelanocytic lesions tend to have homogeneously distributed pigment, while melanocytic lesions contain granules of pigment in cellular inclusions. Any suspicion of melanoma warrants a punch biopsy.¹¹

Medication-induced effects. Minocycline may cause bluish nail discoloration similar to that produced by infection with P aeruginosa, but it is rare for only a single nail to be involved. In addition, pigmentation changes are often present elsewhere on the body, including the sclerae, teeth, and pinna.

Another medication known to color the nails blue is colloidal silver, which is still sold as a dietary supplement or homeopathic remedy to treat a wide range of ailments.⁶ (Of note: In 1999, the Food and Drug Administration issued a final rule saying that colloidal silver isn’t safe or effective for treating any disease or condition.¹²)

Glomus tumor. Another cause of blue nails is glomus tumors, relatively uncommon perivascular neoplasms that are typically found in the subungual region. These tumors are generally accompanied by localized tenderness, cold sensitivity, and paroxysms of excruciating pain that are disproportional to the size of the tumor.

Briefly soaking the nail in a bleach solution helps to suppress bacterial growth.

Imaging studies may aid in the diagnosis, in addition to pathologic confirmation. Magnetic resonance imaging is the most sensitive imaging modality; if a glomus tumor is present, it most often appears as a well-circumscribed T2 hyperintense lesion.¹³

Exogenous pigmentation. Nails may become discolored due to exposure to various toxins or chemicals. Frequent culprits include eosin, methylene blue, henna, hair dye, and tobacco.⁹

Antibiotics and measures to keep the nail dry will help resolve infection

When chronic nail wetness is a contributing factor, treatment begins with measures to keep the nails dry. In addition, either topical or systemic antibiotics may be used to eradicate the infection. Topical applications with agents such as nadifloxacin have been shown to be effective in several case reports,³ but large-scale controlled trials are lacking. Fluoroquinolones are regarded as first-line systemic treatment.⁵ Briefly soaking the nail in a diluted sodium hypochlorite (bleach) solution also helps to suppress bacterial growth. Nail extraction may be required in refractory cases.

For our patient, we prescribed ciprofloxacin 500 mg twice a day for 10 days, plus bleach soaks (one part bleach to 4 parts water) twice a day. We recommended that our patient wear gloves for household tasks that involved immersing her hands in water, and drying her finger with a hair dryer after bathing.

CORRESPONDENCE
David Gish, MD, University of Virginia Health System, 1215 Lee St. Charlottesville, VA 22908; [email protected].

A 34-year-old woman came to our clinic because she was concerned about her thumbnail, which had turned green. Although her finger didn’t hurt, she was bothered by its appearance. Several months earlier, the woman had sought care at a different clinic because the same nail had become brittle and come loose from the nail bed, which was spongy. The physician advised her that she had onychomycosis and prescribed ciclopirox lacquer, but it didn’t help.

Over the next 3 weeks, she noticed a faint green hue developing at the tip of the nail, which expanded and intensified in color (FIGURE). The patient was a mother who worked at home, washed dishes by hand daily, and bathed her children. Her past medical history was significant for type 1 diabetes mellitus and Hashimoto’s thyroiditis. She had no other symptoms.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Green nail syndrome caused by Pseudomonas aeruginosa

This patient had green nail syndrome (GNS), an infection of the nail bed caused by Pseudomonas aeruginosa. These bacteria produce pyocyanin, a blue-green pigment that discolors the nail.¹ GNS often occurs in patients with prior nail problems, such as onychomycosis, onycholysis, trauma, chronic paronychia, or psoriasis.

Nail disease disrupts the integumentary barrier and allows a portal of entry for bacteria. Scanning electron microscopy of patients with GNS has shown that fungal infections create tunnel-like structures in the nail keratin, and P aeruginosa grows in these spaces.² Nails with prior nail disease that are chronically exposed to moisture are at greatest risk of developing GNS,^3,4 and it is typical for only one nail to be involved.⁵Pseudomonas is the most common bacterial infection of the nails, but is not well known because it is rarely reported and patients often don’t seek care.⁶

Pseudomonas is the most common bacterial infection of the nails, but is not well known because it is rarely reported and patients often don't seek care.

In our patient’s case, her prior onychomycosis helped to create a favorable environment for the growth of the bacteria. Onycholysis—characterized by separation of the nail plate from the nail bed—was also present in our patient, based on her description of a “spongy” nail bed and loose nail, allowing moisture and bacteria to infiltrate the space. Onycholysis is associated with hypothyroidism, which the patient also had.⁷ The frequent soaking of her hands during dishwashing and bathing her children helped to provide the moist environment in which Pseudomonas thrives.

As was the case in this patient, GNS is often painless, or may be accompanied by mild tenderness of the nail. Patients may seek treatment primarily for cosmetic reasons.

GNS can be diagnosed by clinical observation and characteristic pigmentation along with an appropriate patient history.⁴ Culture of the nail bed may be helpful if bacterial resistance or co-infection with fungal organisms is suspected.

Changes in nail color can be a sign of many conditions

Nail discoloration, or chromonychia, can present in a variety of colors. Nail findings may represent an isolated disease or provide an important clinical clue to other systemic diseases.⁸ The specific shade of discoloration helps to differentiate the underlying pathology.

Yellow nail syndrome. As the name implies, this syndrome typically causes yellow discoloration of the nail (although yellow-green is also possible). Yellow nail syndrome is believed to be due to microvascular permeability, which also accounts for its associated clinical triad: hypoalbuminemia, pleural effusion, and lymphedema. Yellow nail syndrome may be seen in patients with bronchiectasis, internal malignancies, immunodeficiency, and rheumatoid arthritis.⁸

Nail bed hematoma. Among the most common causes of nail discoloration, these lesions typically appear as reddish to reddish-black, depending on the age of the bleed, and will often have streaks at the distal margin of the lesion.⁹ Risk factors for hemorrhage include blood thinners and clotting disorders. Subungual hemorrhages that do not grow out with the nail, or that recur in the same place, may require biopsy.⁹

Subungual melanoma causes black-brown discoloration of the nails, and may form a longitudinal band in the nail.⁹ Longitudinal melanonychia is a common variant in African American individuals.¹⁰ Features that increase the likelihood of melanoma include a family history of melanoma, a sudden change in the appearance of the lesion, band width greater than 3 mm, pigment changes extending into the cuticle (known as Hutchinson’s sign), and nail plate disruption.

Dermoscopy, the technique of using surface microscopy to examine the skin, may be helpful in distinguishing nail lesions. (See a video on how to perform dermoscopy here: http://bit.ly/2pyJ3xN.)

Nonmelanocytic lesions tend to have homogeneously distributed pigment, while melanocytic lesions contain granules of pigment in cellular inclusions. Any suspicion of melanoma warrants a punch biopsy.¹¹

Medication-induced effects. Minocycline may cause bluish nail discoloration similar to that produced by infection with P aeruginosa, but it is rare for only a single nail to be involved. In addition, pigmentation changes are often present elsewhere on the body, including the sclerae, teeth, and pinna.

Another medication known to color the nails blue is colloidal silver, which is still sold as a dietary supplement or homeopathic remedy to treat a wide range of ailments.⁶ (Of note: In 1999, the Food and Drug Administration issued a final rule saying that colloidal silver isn’t safe or effective for treating any disease or condition.¹²)

Glomus tumor. Another cause of blue nails is glomus tumors, relatively uncommon perivascular neoplasms that are typically found in the subungual region. These tumors are generally accompanied by localized tenderness, cold sensitivity, and paroxysms of excruciating pain that are disproportional to the size of the tumor.

Briefly soaking the nail in a bleach solution helps to suppress bacterial growth.

Imaging studies may aid in the diagnosis, in addition to pathologic confirmation. Magnetic resonance imaging is the most sensitive imaging modality; if a glomus tumor is present, it most often appears as a well-circumscribed T2 hyperintense lesion.¹³

Exogenous pigmentation. Nails may become discolored due to exposure to various toxins or chemicals. Frequent culprits include eosin, methylene blue, henna, hair dye, and tobacco.⁹

Antibiotics and measures to keep the nail dry will help resolve infection

When chronic nail wetness is a contributing factor, treatment begins with measures to keep the nails dry. In addition, either topical or systemic antibiotics may be used to eradicate the infection. Topical applications with agents such as nadifloxacin have been shown to be effective in several case reports,³ but large-scale controlled trials are lacking. Fluoroquinolones are regarded as first-line systemic treatment.⁵ Briefly soaking the nail in a diluted sodium hypochlorite (bleach) solution also helps to suppress bacterial growth. Nail extraction may be required in refractory cases.

For our patient, we prescribed ciprofloxacin 500 mg twice a day for 10 days, plus bleach soaks (one part bleach to 4 parts water) twice a day. We recommended that our patient wear gloves for household tasks that involved immersing her hands in water, and drying her finger with a hair dryer after bathing.

CORRESPONDENCE
David Gish, MD, University of Virginia Health System, 1215 Lee St. Charlottesville, VA 22908; [email protected].

A 59-year-old woman presented to our emergency department with a rash, severe acute pain in her left hip and lower back, and dyspnea on exertion. She denied having a headache and her mental status was at baseline. The woman reported exposure to rats and snakes one week prior to presentation, and mentioned getting bitten by a rat multiple times on the back of both of her hands while feeding it to her son’s pet snake. The patient had a history of a left hip replacement, with a revision and bone graft 5 years earlier.

The patient had a fever of 103° F during the physical examination. She had erythematous papules and central hemorrhagic eschars at the sites of the bites (FIGURE 1). She also had nonblanching petechiae on both of her lower legs (FIGURE 2) and on the dorsal and palmar aspects of her hands.

The patient’s lab work showed mild normocytic anemia with a hemoglobin level of 11.4 g/dL (normal, 12-16 g/dL) and a platelet count of 129,000/mcL (normal, 130,000-400,000/mcL). Her white blood cell count, chemistries, brain natriuretic peptide test, and chest x-ray were normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Rat bite fever

Based on the patient’s symptoms, history, and lab work, we concluded that this was a case of rat bite fever. RBF is a zoonotic systemic illness caused by infection from either the gram-negative bacillus Streptobacillus moniliformis, commonly found in the United States, or the gram-negative rod Spirillum minus, commonly seen in Asia. Anyone with exposure to rats is at risk for RBF, especially pet shop employees, lab workers, and people living in areas with rat infestations.¹

The rash associated with RBF can be petechial, purpuric, or maculopapular, but the presence of hemorrhagic nodules and ulcers at the site of the bite is especially indicative of the illness. The rash often involves the hands and feet, including the palms and soles.

To make the diagnosis of RBF, a careful history and a high index of suspicion are important. Fever and rigor are often the first symptoms to appear, beginning 3 to 10 days after the bite. Three to 4 days after the onset of fever, up to 75% of patients will develop a rash.² Joint and muscle aches are also common, as is a migrating pattern of arthritis.^2,3

Rule out other infections related to animal exposure

The differential diagnosis for RBF includes other animal-related infections, such as those from snake bites, leptospirosis, rabies, and pasteurellosis.

Symptoms associated with snake bite injuries appear rapidly after the bite and vary with the type of snake toxin. Hemotoxic symptoms may include intense pain, edema, petechiae, and ecchymosis from coagulopathy. Neurotoxic symptoms may include ptosis, weakness, and paresthesias. All snake bites should be treated with supportive care, and antivenin is indicated when symptoms or history indicate a bite from a venomous snake. Venomous snakes are rarely intentionally kept as pets.²

Leptospirosis is a zoonotic bacterial infection that may be spread through the urine of rats, dogs, or other mammals. Symptoms may be mild and limited to conjunctivitis, vomiting, and fever; life-threatening symptoms include hemorrhage and kidney failure. A petechial rash is not typical.⁴ Beta-lactam antibiotics are the treatment of choice.

Rabies is a viral infection that occurs after exposure to infected animals (most commonly raccoons, bats, skunks, and foxes). Symptoms include fever and mental status changes that can lead to death; rash is not a typical symptom. Exposed patients should receive post-exposure prophylaxis with immune globulin or a rabies vaccine.⁵

Pasteurellosis may also cause hemorrhagic nodules at the site of the bite or scratch, but bites are typically caused by larger animals such as dogs and livestock. Other symptoms include fever, sepsis, and osteomyelitis. Treatment includes amoxicillin-clavulanate or a fluoroquinolone-clindamycin combination.⁶

In cases of high suspicion, special culture tubes may be needed

Blood cultures and cerebrospinal fluid cultures are often falsely negative. Special culture tubes without polyanethol sulfonate preservative, which inhibits the growth of S moniliformis, may be required in cases of high suspicion. S moniliformis polymerase chain reaction may be available in some specialized labs.^7,8

Treatment options include 7 to 10 days of antibiotic therapy with oral penicillin 500 mg 4 times daily, amoxicillin-clavulanate 875/125 mg twice daily, or oral doxycycline 100 mg every 12 hours.⁹

RBF may be fatal if not treated.³ Complications may include bacteremia, septicemia, meningitis, and endocarditis.

Our patient received empiric intravenous ceftriaxone 1 g every 24 hours and her fever and joint pain resolved within 48 hours. On Day 3 she was discharged home to complete a 10-day course of oral amoxicillin-clavulanate 875/125 mg. Her primary care physician reported that the rash resolved and the patient made a full recovery.

CORRESPONDENCE
Kate Rowland, MD, MS, Rush-Copley Family Medicine Residency, 2020 Ogden Ave. Suite 325, Aurora, IL 60504; [email protected].

A 59-year-old woman presented to our emergency department with a rash, severe acute pain in her left hip and lower back, and dyspnea on exertion. She denied having a headache and her mental status was at baseline. The woman reported exposure to rats and snakes one week prior to presentation, and mentioned getting bitten by a rat multiple times on the back of both of her hands while feeding it to her son’s pet snake. The patient had a history of a left hip replacement, with a revision and bone graft 5 years earlier.

The patient had a fever of 103° F during the physical examination. She had erythematous papules and central hemorrhagic eschars at the sites of the bites (FIGURE 1). She also had nonblanching petechiae on both of her lower legs (FIGURE 2) and on the dorsal and palmar aspects of her hands.

The patient’s lab work showed mild normocytic anemia with a hemoglobin level of 11.4 g/dL (normal, 12-16 g/dL) and a platelet count of 129,000/mcL (normal, 130,000-400,000/mcL). Her white blood cell count, chemistries, brain natriuretic peptide test, and chest x-ray were normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Rat bite fever

Based on the patient’s symptoms, history, and lab work, we concluded that this was a case of rat bite fever. RBF is a zoonotic systemic illness caused by infection from either the gram-negative bacillus Streptobacillus moniliformis, commonly found in the United States, or the gram-negative rod Spirillum minus, commonly seen in Asia. Anyone with exposure to rats is at risk for RBF, especially pet shop employees, lab workers, and people living in areas with rat infestations.¹

The rash associated with RBF can be petechial, purpuric, or maculopapular, but the presence of hemorrhagic nodules and ulcers at the site of the bite is especially indicative of the illness. The rash often involves the hands and feet, including the palms and soles.

To make the diagnosis of RBF, a careful history and a high index of suspicion are important. Fever and rigor are often the first symptoms to appear, beginning 3 to 10 days after the bite. Three to 4 days after the onset of fever, up to 75% of patients will develop a rash.² Joint and muscle aches are also common, as is a migrating pattern of arthritis.^2,3

Rule out other infections related to animal exposure

The differential diagnosis for RBF includes other animal-related infections, such as those from snake bites, leptospirosis, rabies, and pasteurellosis.

Symptoms associated with snake bite injuries appear rapidly after the bite and vary with the type of snake toxin. Hemotoxic symptoms may include intense pain, edema, petechiae, and ecchymosis from coagulopathy. Neurotoxic symptoms may include ptosis, weakness, and paresthesias. All snake bites should be treated with supportive care, and antivenin is indicated when symptoms or history indicate a bite from a venomous snake. Venomous snakes are rarely intentionally kept as pets.²

Leptospirosis is a zoonotic bacterial infection that may be spread through the urine of rats, dogs, or other mammals. Symptoms may be mild and limited to conjunctivitis, vomiting, and fever; life-threatening symptoms include hemorrhage and kidney failure. A petechial rash is not typical.⁴ Beta-lactam antibiotics are the treatment of choice.

Rabies is a viral infection that occurs after exposure to infected animals (most commonly raccoons, bats, skunks, and foxes). Symptoms include fever and mental status changes that can lead to death; rash is not a typical symptom. Exposed patients should receive post-exposure prophylaxis with immune globulin or a rabies vaccine.⁵

Pasteurellosis may also cause hemorrhagic nodules at the site of the bite or scratch, but bites are typically caused by larger animals such as dogs and livestock. Other symptoms include fever, sepsis, and osteomyelitis. Treatment includes amoxicillin-clavulanate or a fluoroquinolone-clindamycin combination.⁶

In cases of high suspicion, special culture tubes may be needed

Blood cultures and cerebrospinal fluid cultures are often falsely negative. Special culture tubes without polyanethol sulfonate preservative, which inhibits the growth of S moniliformis, may be required in cases of high suspicion. S moniliformis polymerase chain reaction may be available in some specialized labs.^7,8

Treatment options include 7 to 10 days of antibiotic therapy with oral penicillin 500 mg 4 times daily, amoxicillin-clavulanate 875/125 mg twice daily, or oral doxycycline 100 mg every 12 hours.⁹

RBF may be fatal if not treated.³ Complications may include bacteremia, septicemia, meningitis, and endocarditis.

Our patient received empiric intravenous ceftriaxone 1 g every 24 hours and her fever and joint pain resolved within 48 hours. On Day 3 she was discharged home to complete a 10-day course of oral amoxicillin-clavulanate 875/125 mg. Her primary care physician reported that the rash resolved and the patient made a full recovery.

CORRESPONDENCE
Kate Rowland, MD, MS, Rush-Copley Family Medicine Residency, 2020 Ogden Ave. Suite 325, Aurora, IL 60504; [email protected].

A 59-year-old woman presented to our emergency department with a rash, severe acute pain in her left hip and lower back, and dyspnea on exertion. She denied having a headache and her mental status was at baseline. The woman reported exposure to rats and snakes one week prior to presentation, and mentioned getting bitten by a rat multiple times on the back of both of her hands while feeding it to her son’s pet snake. The patient had a history of a left hip replacement, with a revision and bone graft 5 years earlier.

The patient had a fever of 103° F during the physical examination. She had erythematous papules and central hemorrhagic eschars at the sites of the bites (FIGURE 1). She also had nonblanching petechiae on both of her lower legs (FIGURE 2) and on the dorsal and palmar aspects of her hands.

The patient’s lab work showed mild normocytic anemia with a hemoglobin level of 11.4 g/dL (normal, 12-16 g/dL) and a platelet count of 129,000/mcL (normal, 130,000-400,000/mcL). Her white blood cell count, chemistries, brain natriuretic peptide test, and chest x-ray were normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Rat bite fever

Based on the patient’s symptoms, history, and lab work, we concluded that this was a case of rat bite fever. RBF is a zoonotic systemic illness caused by infection from either the gram-negative bacillus Streptobacillus moniliformis, commonly found in the United States, or the gram-negative rod Spirillum minus, commonly seen in Asia. Anyone with exposure to rats is at risk for RBF, especially pet shop employees, lab workers, and people living in areas with rat infestations.¹

The rash associated with RBF can be petechial, purpuric, or maculopapular, but the presence of hemorrhagic nodules and ulcers at the site of the bite is especially indicative of the illness. The rash often involves the hands and feet, including the palms and soles.

To make the diagnosis of RBF, a careful history and a high index of suspicion are important. Fever and rigor are often the first symptoms to appear, beginning 3 to 10 days after the bite. Three to 4 days after the onset of fever, up to 75% of patients will develop a rash.² Joint and muscle aches are also common, as is a migrating pattern of arthritis.^2,3

Rule out other infections related to animal exposure

The differential diagnosis for RBF includes other animal-related infections, such as those from snake bites, leptospirosis, rabies, and pasteurellosis.

Symptoms associated with snake bite injuries appear rapidly after the bite and vary with the type of snake toxin. Hemotoxic symptoms may include intense pain, edema, petechiae, and ecchymosis from coagulopathy. Neurotoxic symptoms may include ptosis, weakness, and paresthesias. All snake bites should be treated with supportive care, and antivenin is indicated when symptoms or history indicate a bite from a venomous snake. Venomous snakes are rarely intentionally kept as pets.²

Leptospirosis is a zoonotic bacterial infection that may be spread through the urine of rats, dogs, or other mammals. Symptoms may be mild and limited to conjunctivitis, vomiting, and fever; life-threatening symptoms include hemorrhage and kidney failure. A petechial rash is not typical.⁴ Beta-lactam antibiotics are the treatment of choice.

Rabies is a viral infection that occurs after exposure to infected animals (most commonly raccoons, bats, skunks, and foxes). Symptoms include fever and mental status changes that can lead to death; rash is not a typical symptom. Exposed patients should receive post-exposure prophylaxis with immune globulin or a rabies vaccine.⁵

Pasteurellosis may also cause hemorrhagic nodules at the site of the bite or scratch, but bites are typically caused by larger animals such as dogs and livestock. Other symptoms include fever, sepsis, and osteomyelitis. Treatment includes amoxicillin-clavulanate or a fluoroquinolone-clindamycin combination.⁶

In cases of high suspicion, special culture tubes may be needed

Blood cultures and cerebrospinal fluid cultures are often falsely negative. Special culture tubes without polyanethol sulfonate preservative, which inhibits the growth of S moniliformis, may be required in cases of high suspicion. S moniliformis polymerase chain reaction may be available in some specialized labs.^7,8

Treatment options include 7 to 10 days of antibiotic therapy with oral penicillin 500 mg 4 times daily, amoxicillin-clavulanate 875/125 mg twice daily, or oral doxycycline 100 mg every 12 hours.⁹

RBF may be fatal if not treated.³ Complications may include bacteremia, septicemia, meningitis, and endocarditis.

Our patient received empiric intravenous ceftriaxone 1 g every 24 hours and her fever and joint pain resolved within 48 hours. On Day 3 she was discharged home to complete a 10-day course of oral amoxicillin-clavulanate 875/125 mg. Her primary care physician reported that the rash resolved and the patient made a full recovery.

CORRESPONDENCE
Kate Rowland, MD, MS, Rush-Copley Family Medicine Residency, 2020 Ogden Ave. Suite 325, Aurora, IL 60504; [email protected].

THE CASE

A 32-year-old Chinese woman sought care from our family medicine clinic because she had a headache, neck pain, and an intermittent cough that had produced white sputum for 7 days. She described the headache as severe and pressure-like, and said that it had progressively worsened over the previous 3 weeks, coinciding with her first trip outside of China to the United States. The patient indicated that she also had occasional vomiting, dizziness, a low-grade fever, chills, night sweats, and increasing fatigue.

Prior to this visit, the patient had gone to the emergency department (ED) twice in one week, but was told that she had a migraine headache and a viral syndrome and was sent home. She was also told to make a follow-up appointment at our family medicine outpatient clinic.

Besides the symptoms that brought her to our clinic, the only other notable element of the patient’s history was a “neck mass” resection in China 8 years earlier. (The diagnosis of the neck mass was unknown.)

Concerned about her presenting signs and symptoms, we sent the patient to the ED, where she was admitted for further evaluation and treatment of possible meningitis. In the ED, she had a temperature of 101.5° F; her other vital signs were normal. A physical exam revealed mild neck stiffness.

THE DIAGNOSIS

A chest computed tomography (CT) scan demonstrated extensive confluent nodular infiltrates in the lung apices bilaterally with the largest confluent nodule measuring 6 cm (FIGURE 1). A chest x-ray demonstrated extensive bilateral pulmonary interstitial infiltrates that were most pronounced in the upper lung fields (FIGURE 2).

Lumbar puncture results revealed lymphocytic pleocytosis with elevated protein and low glucose levels (TABLE). Based on these results, the family medicine team suspected that our patient had tuberculous meningitis (TBM).

The team consulted with Infectious Diseases for management of TBM, and they placed our patient in a negative pressure room on airborne isolation. In addition, she was started on rifampin 450 mg/d, pyrazinamide 1000 mg/d, ethambutol 800 mg/d, and isoniazid (INH) 800 mg/d, as well as pyridoxine and intravenous dexamethasone.

DISCUSSION

TBM accounts for approximately 1% of all cases of TB and 5% of extrapulmonary diseases in immunocompetent individuals.¹ In 2015, there were approximately 10.4 million cases of TB worldwide, and 6 countries accounted for 60% of the global total: India, Indonesia, China, Nigeria, Pakistan, and South Africa.² TBM is typically a subacute disease with symptoms that can persist for weeks before diagnosis.³ An early diagnosis is critical, as the mortality rate remains relatively high (as high as nearly 70% in underdeveloped and developed countries) despite effective treatment regimens.³ (For updated recommendations on TB screening, see this month’s Practice Alert.)

Once you suspect tuberculous meningitis, isolate the patient, obtain appropriate cultures and smears, and start anti-tuberculosis drugs and adjunctive corticosteroids immediately.

Most health care facilities use AFB smears to determine when patients with suspected TB should be isolated. However, AFB smears are positive in only 60% of TB cases.⁴ One study indicated that nucleic acid amplification by PCR can improve sensitivity from 60% to 87% and specificity from 98% to 100%.⁵

The presentation of TBM varies by phase of disease:

• The prodromal phase typically lasts for 2 to 3 weeks. It is characterized by an insidious onset of malaise, headache, low-grade fever, irritability, and personality changes.
• The meningitis phase is characterized by pronounced neurologic features such as meningismus, protracted headache, confusion, myelopathy, and sensory deficits, as well as vomiting, lethargy, and urinary retention.
• During the paralytic phase, patients experience profound confusion, followed by stupor, coma, seizures, progressive paraplegia, and often, hemiparesis.^1,3,6

Treatment should be given for a total of 9 to 12 months

Initiate treatment for TB based on a strong clinical suspicion for the disease. Treatment of TBM consists of an intensive phase with 4 anti-TB drugs for 2 months (typically INH 800 mg/d, rifampin 450 mg/d, pyrazinamide 1000 mg/d, and ethambutol 800 mg/d) and a continuation phase with 2 drugs (INH and rifampin) for 7 to 10 additional months, resulting in a total treatment duration of 9 to 12 months.

Our patient was discharged from the hospital after 2 weeks on an anti-TB medication regimen of INH, rifampin, and pyrazinamide, along with pyridoxine and a tapering dose of dexamethasone. After the initial 2 months of intensive phase therapy, she was switched to INH 300 mg/d and rifampin 450 mg/d for the continuation phase. The patient followed up at our family medicine outpatient clinic with slow improvement of her muscle weakness before returning to China once she was placed on the continuation phase drugs.

THE TAKEAWAY

Suspect TB in high-risk patients traveling from endemic areas. Our patient, a Chinese woman visiting Brooklyn, New York, should’ve been considered high risk for TB even without her travel history from China because Brooklyn has a high rate of TB, as well. (In 2015, Sunset Park, Brooklyn had 18.2 cases of TB per 100,000 people, which was more than double the citywide rate.⁷)

TBM is a subacute disease with an often subtle presentation. Once you suspect TBM, isolate the patient, obtain appropriate cultures and smears, and start anti-TB drugs and adjunctive corticosteroids immediately, while the results of studies for AFB are still pending. Prompt diagnosis and treatment can save a patient’s life.

THE CASE

A 32-year-old Chinese woman sought care from our family medicine clinic because she had a headache, neck pain, and an intermittent cough that had produced white sputum for 7 days. She described the headache as severe and pressure-like, and said that it had progressively worsened over the previous 3 weeks, coinciding with her first trip outside of China to the United States. The patient indicated that she also had occasional vomiting, dizziness, a low-grade fever, chills, night sweats, and increasing fatigue.

Prior to this visit, the patient had gone to the emergency department (ED) twice in one week, but was told that she had a migraine headache and a viral syndrome and was sent home. She was also told to make a follow-up appointment at our family medicine outpatient clinic.

Besides the symptoms that brought her to our clinic, the only other notable element of the patient’s history was a “neck mass” resection in China 8 years earlier. (The diagnosis of the neck mass was unknown.)

Concerned about her presenting signs and symptoms, we sent the patient to the ED, where she was admitted for further evaluation and treatment of possible meningitis. In the ED, she had a temperature of 101.5° F; her other vital signs were normal. A physical exam revealed mild neck stiffness.

THE DIAGNOSIS

A chest computed tomography (CT) scan demonstrated extensive confluent nodular infiltrates in the lung apices bilaterally with the largest confluent nodule measuring 6 cm (FIGURE 1). A chest x-ray demonstrated extensive bilateral pulmonary interstitial infiltrates that were most pronounced in the upper lung fields (FIGURE 2).

Lumbar puncture results revealed lymphocytic pleocytosis with elevated protein and low glucose levels (TABLE). Based on these results, the family medicine team suspected that our patient had tuberculous meningitis (TBM).

The team consulted with Infectious Diseases for management of TBM, and they placed our patient in a negative pressure room on airborne isolation. In addition, she was started on rifampin 450 mg/d, pyrazinamide 1000 mg/d, ethambutol 800 mg/d, and isoniazid (INH) 800 mg/d, as well as pyridoxine and intravenous dexamethasone.

DISCUSSION

TBM accounts for approximately 1% of all cases of TB and 5% of extrapulmonary diseases in immunocompetent individuals.¹ In 2015, there were approximately 10.4 million cases of TB worldwide, and 6 countries accounted for 60% of the global total: India, Indonesia, China, Nigeria, Pakistan, and South Africa.² TBM is typically a subacute disease with symptoms that can persist for weeks before diagnosis.³ An early diagnosis is critical, as the mortality rate remains relatively high (as high as nearly 70% in underdeveloped and developed countries) despite effective treatment regimens.³ (For updated recommendations on TB screening, see this month’s Practice Alert.)

Once you suspect tuberculous meningitis, isolate the patient, obtain appropriate cultures and smears, and start anti-tuberculosis drugs and adjunctive corticosteroids immediately.

Most health care facilities use AFB smears to determine when patients with suspected TB should be isolated. However, AFB smears are positive in only 60% of TB cases.⁴ One study indicated that nucleic acid amplification by PCR can improve sensitivity from 60% to 87% and specificity from 98% to 100%.⁵

The presentation of TBM varies by phase of disease:

• The prodromal phase typically lasts for 2 to 3 weeks. It is characterized by an insidious onset of malaise, headache, low-grade fever, irritability, and personality changes.
• The meningitis phase is characterized by pronounced neurologic features such as meningismus, protracted headache, confusion, myelopathy, and sensory deficits, as well as vomiting, lethargy, and urinary retention.
• During the paralytic phase, patients experience profound confusion, followed by stupor, coma, seizures, progressive paraplegia, and often, hemiparesis.^1,3,6

Treatment should be given for a total of 9 to 12 months

Initiate treatment for TB based on a strong clinical suspicion for the disease. Treatment of TBM consists of an intensive phase with 4 anti-TB drugs for 2 months (typically INH 800 mg/d, rifampin 450 mg/d, pyrazinamide 1000 mg/d, and ethambutol 800 mg/d) and a continuation phase with 2 drugs (INH and rifampin) for 7 to 10 additional months, resulting in a total treatment duration of 9 to 12 months.

Our patient was discharged from the hospital after 2 weeks on an anti-TB medication regimen of INH, rifampin, and pyrazinamide, along with pyridoxine and a tapering dose of dexamethasone. After the initial 2 months of intensive phase therapy, she was switched to INH 300 mg/d and rifampin 450 mg/d for the continuation phase. The patient followed up at our family medicine outpatient clinic with slow improvement of her muscle weakness before returning to China once she was placed on the continuation phase drugs.

THE TAKEAWAY

Suspect TB in high-risk patients traveling from endemic areas. Our patient, a Chinese woman visiting Brooklyn, New York, should’ve been considered high risk for TB even without her travel history from China because Brooklyn has a high rate of TB, as well. (In 2015, Sunset Park, Brooklyn had 18.2 cases of TB per 100,000 people, which was more than double the citywide rate.⁷)

TBM is a subacute disease with an often subtle presentation. Once you suspect TBM, isolate the patient, obtain appropriate cultures and smears, and start anti-TB drugs and adjunctive corticosteroids immediately, while the results of studies for AFB are still pending. Prompt diagnosis and treatment can save a patient’s life.

THE CASE

A 32-year-old Chinese woman sought care from our family medicine clinic because she had a headache, neck pain, and an intermittent cough that had produced white sputum for 7 days. She described the headache as severe and pressure-like, and said that it had progressively worsened over the previous 3 weeks, coinciding with her first trip outside of China to the United States. The patient indicated that she also had occasional vomiting, dizziness, a low-grade fever, chills, night sweats, and increasing fatigue.

Prior to this visit, the patient had gone to the emergency department (ED) twice in one week, but was told that she had a migraine headache and a viral syndrome and was sent home. She was also told to make a follow-up appointment at our family medicine outpatient clinic.

Besides the symptoms that brought her to our clinic, the only other notable element of the patient’s history was a “neck mass” resection in China 8 years earlier. (The diagnosis of the neck mass was unknown.)

Concerned about her presenting signs and symptoms, we sent the patient to the ED, where she was admitted for further evaluation and treatment of possible meningitis. In the ED, she had a temperature of 101.5° F; her other vital signs were normal. A physical exam revealed mild neck stiffness.

THE DIAGNOSIS

A chest computed tomography (CT) scan demonstrated extensive confluent nodular infiltrates in the lung apices bilaterally with the largest confluent nodule measuring 6 cm (FIGURE 1). A chest x-ray demonstrated extensive bilateral pulmonary interstitial infiltrates that were most pronounced in the upper lung fields (FIGURE 2).

Lumbar puncture results revealed lymphocytic pleocytosis with elevated protein and low glucose levels (TABLE). Based on these results, the family medicine team suspected that our patient had tuberculous meningitis (TBM).

The team consulted with Infectious Diseases for management of TBM, and they placed our patient in a negative pressure room on airborne isolation. In addition, she was started on rifampin 450 mg/d, pyrazinamide 1000 mg/d, ethambutol 800 mg/d, and isoniazid (INH) 800 mg/d, as well as pyridoxine and intravenous dexamethasone.

DISCUSSION

TBM accounts for approximately 1% of all cases of TB and 5% of extrapulmonary diseases in immunocompetent individuals.¹ In 2015, there were approximately 10.4 million cases of TB worldwide, and 6 countries accounted for 60% of the global total: India, Indonesia, China, Nigeria, Pakistan, and South Africa.² TBM is typically a subacute disease with symptoms that can persist for weeks before diagnosis.³ An early diagnosis is critical, as the mortality rate remains relatively high (as high as nearly 70% in underdeveloped and developed countries) despite effective treatment regimens.³ (For updated recommendations on TB screening, see this month’s Practice Alert.)

Once you suspect tuberculous meningitis, isolate the patient, obtain appropriate cultures and smears, and start anti-tuberculosis drugs and adjunctive corticosteroids immediately.

Most health care facilities use AFB smears to determine when patients with suspected TB should be isolated. However, AFB smears are positive in only 60% of TB cases.⁴ One study indicated that nucleic acid amplification by PCR can improve sensitivity from 60% to 87% and specificity from 98% to 100%.⁵

The presentation of TBM varies by phase of disease:

• The prodromal phase typically lasts for 2 to 3 weeks. It is characterized by an insidious onset of malaise, headache, low-grade fever, irritability, and personality changes.
• The meningitis phase is characterized by pronounced neurologic features such as meningismus, protracted headache, confusion, myelopathy, and sensory deficits, as well as vomiting, lethargy, and urinary retention.
• During the paralytic phase, patients experience profound confusion, followed by stupor, coma, seizures, progressive paraplegia, and often, hemiparesis.^1,3,6

Treatment should be given for a total of 9 to 12 months

Initiate treatment for TB based on a strong clinical suspicion for the disease. Treatment of TBM consists of an intensive phase with 4 anti-TB drugs for 2 months (typically INH 800 mg/d, rifampin 450 mg/d, pyrazinamide 1000 mg/d, and ethambutol 800 mg/d) and a continuation phase with 2 drugs (INH and rifampin) for 7 to 10 additional months, resulting in a total treatment duration of 9 to 12 months.

Our patient was discharged from the hospital after 2 weeks on an anti-TB medication regimen of INH, rifampin, and pyrazinamide, along with pyridoxine and a tapering dose of dexamethasone. After the initial 2 months of intensive phase therapy, she was switched to INH 300 mg/d and rifampin 450 mg/d for the continuation phase. The patient followed up at our family medicine outpatient clinic with slow improvement of her muscle weakness before returning to China once she was placed on the continuation phase drugs.

THE TAKEAWAY

Suspect TB in high-risk patients traveling from endemic areas. Our patient, a Chinese woman visiting Brooklyn, New York, should’ve been considered high risk for TB even without her travel history from China because Brooklyn has a high rate of TB, as well. (In 2015, Sunset Park, Brooklyn had 18.2 cases of TB per 100,000 people, which was more than double the citywide rate.⁷)

TBM is a subacute disease with an often subtle presentation. Once you suspect TBM, isolate the patient, obtain appropriate cultures and smears, and start anti-TB drugs and adjunctive corticosteroids immediately, while the results of studies for AFB are still pending. Prompt diagnosis and treatment can save a patient’s life.