HIV, Baby, and Me: Preventing Perinatal Transmission of HIV-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-9999-24-024-H02-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

1. A 24-year-old female living with HIV is interested in having children and is concerned about perinatal transmission. Her HIV viral load is currently undetectable by adherence to antiretroviral therapy (ART). Is it possible for HIV mothers to breastfeed their babies, assuming the babies do not contract HIV during childbirth?

A. Yes, as long as the mother’s viral load is undetectable at <50 copies/mL
B. Yes, as long as the mother’s viral load is undetectable at <200 copies/mL
C. No, the baby can still contract HIV even if the mother’s viral load is undetectable at <200 copies/mL

2. Maria, a 29-year-old woman living with HIV has been on a stable ART regimen for the past two years. During her recent check-up, she reported experiencing significant nausea and fatigue from her medication. She is currently in her first trimester of pregnancy and is considering stopping her ART due to these side effects. What should be the primary course of action for Maria's healthcare provider to ensure both her health and the health of her unborn child?

A. Encourage Maria to discontinue her ART temporarily while she consults with a nutritionist to address her side effects, assuming that her HIV will remain under control during this period.
B. Assess and manage Maria's current side effects and explore alternative ART options or supportive treatments that can alleviate her symptoms, ensure continued viral suppression, and minimize risks to her pregnancy.
C. Reassure Maria that side effects are temporary and advise her to continue with the current ART regimen without making any changes, regardless of her concerns or symptoms.

3. Samantha, a 30-year-old woman, is newly diagnosed with HIV and is currently in her first trimester of pregnancy. She has not started any ART and refused to take any medication. A couple of weeks later, after listening to the pharmacist's consultation, Samantha is now concerned about choosing a regimen that will be both effective and safe for her and her unborn child. Which of the following ART regimens would be the most appropriate initial choice for Samantha based on current guidelines and safety considerations?

A. Tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) + abacarvir
B. Abacavir + lamivudine
C. Tenofovir disoproxil fumarate (TDF) + lamivudine + dolutegravir

4. Emily, a 34-year-old woman living with HIV, is pregnant and is currently adherent to ART. During her recent check-up, her healthcare provider confirmed that her HIV viral load is undetectable. However, she is still worried about the possibility of HIV transmission to her baby during pregnancy phases and wants to understand the implications of her undetectable viral load for her baby’s health. Which of the following statements accurately reflects the risk of HIV transmission to her baby during pregnancy, childbirth, and breastfeeding?

A. With an undetectable viral load, Emily is at a high risk of transmitting HIV to the baby during her pregnancy phases because it’s hard to know if her condition is under control.
B. There is no risk of HIV transmission to the baby during pregnancy, childbirth, or breastfeeding, provided that ART is consistently taken and the viral load remains undetectable.
C. Emily can transmit HIV to her baby during pregnancy, but the risk is low if her viral load remains undetectable throughout her pregnancy.

5. A 23-month-old boy living with HIV is starting a new regimen next month. The new regimen is an INSTI-based regimen with the anchor drug being dolutegravir plus FTC/TAF in FDC (Descovy). What verification(s) is/are required before filling this order?

A. Mother’s viral load is <50 copies/mL
B. Patient’s viral load is between 50 to 200 copies/mL
C. Weight + Route of administration

6. What is the key difference between opt-in and opt-out HIV screening?

A. Specificity
B. Stages of infection
C. The assumption of Consent-longest…can we just say “consent”?

7. A postpartum patient with HIV is in her 6-week follow-up visit. She is adhering well to her ART but expresses concern about her contraceptive options and the feeding of her newborn. Which of the following recommendations is the best course of action for her situation?

A. Recommend that she exclusively uses barrier methods for contraception to avoid any potential interaction with her ART.
B. Inform her that donor human milk is a safe option for her baby, provided it is obtained from a reputable milk bank and properly pasteurized.
C. Suggest that she avoid all forms of hormonal contraception due to potential drug interactions with her ART regimen.

Understanding Treatment Approaches for Autism Spectrum Disorder

After completing this application-based continuing education activity, pharmacists will be able to

DESCRIBE autism spectrum disorder (ASD) and its manifestations

LIST medications used to manage symptoms of ASD

APPLY techniques to improve care in the pharmacy for patients with ASD and their caretakers

After completing this application-based continuing education activity, pharmacy technicians will be able to

DESCRIBE autism spectrum disorder (ASD) and its manifestations

LIST medications used to manage symptoms of ASD

RECOGNIZE situations in which they can help patients with ASD and their caretakers appropriately

Our understanding of "autism" has evolved from the early 1900s when it was originally described as childhood schizophrenia. Although classified as an independent condition in the DSM-III in 1980, the DSM-V consolidated autistic disorder, Asperger syndrome, pervasive developmental disorder—not otherwise specified, and childhood disintegrative disorder into the term known as autism spectrum disorder (ASD). This has left many healthcare providers confused about the diagnosis and its treatment. Pharmacists and pharmacy technicians need tools so that they will be able to communicate with and help people who have ASD. In addition, they need to have science- based information about the treatments used in ASD, and the indications for which they are employed. It also introduces and expands upon the terms neurotypical and neurodiverse.

INTRODUCTION

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent challenges in social interaction and communication, and restricted, repetitive patterns of behavior, interests, or activities. “Autism” has evolved from the early 1900s, when it was originally described as childhood schizophrenia in the first and second editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM).¹Autism was classified as an independent condition in the DSM-III in 1980. The DSM-IV in 1994 was the first to recognize autism as a spectrum with various distinct diagnoses. In 2013, the DSM-V consolidated autistic disorder, Asperger syndrome, pervasive developmental disorder-not otherwise specified, and childhood disintegrative disorder into the term known as autism spectrum disorder.²

The change in terminology has left many healthcare providers unsure about how to talk with and about people who have ASD. Researchers from the United Kingdom surveyed 654 English-speaking adults with ASD around the world to determine their preferences.³ Regardless of country, participants tended to favor the terms autism, autistic person, is autistic, neurological/brain difference, differences, challenges, difficulties, neurotypical people, and neurotypicals. Thus, the researchers were unable to find a universally accepted vernacular to talk about autism.³ Perhaps the best way to determine how to describe a patient with ASD is to ask how they themselves prefer to discuss their condition.

The term neurotypical is closely related to the term neurodiverse, and the SIDEBAR describes this relatively new term.

SIDEBAR: Neurodiversity^4-7

Medical insight and social changes in the perception of developmental disorders and neurodevelopmental trajectories, including the autism spectrum, have led to a changing vocabulary and a deeper appreciation of what is “normal.” Increasingly, we understand that human development is neurodiverse, meaning all individuals develop and behave differently. The concept of neurodiversity promotes the idea that people who have neurological limitations also have strengths, and that accommodating their differences as early in life as possible can be beneficial to the individual and to society at large. This is an empathetic, humanistic, tolerant approach.

It's now clear that people with ASD are often skilled in working with systems and finding patterns in complex data or material. This makes them good candidates to work in technology and manufacturing if an employer can accommodate an individual’s needs (e.g., quiet or dimly lit spaces, private or uncrowded work areas). People with dyslexia are often better than others at identifying peripheral or diffuse visual information or processing blurry visual scenes, making them excellent candidates for jobs that engage three-dimensional thinking (e.g., computer graphics, engineering, genetics, or molecular biology). Similarly, people with Williams syndrome (a rare genetic condition that affects physical features, development, and cardiovascular health), Down syndrome, and Prader-Willi syndrome (a rare genetic disorder causing weak muscles, poor feeding, and slow development in infants followed by constant hunger in childhood), tend to be more musical, more friendly, and more nurturing than others, respectively. Researchers have also connected specific strengths to other neurologic and intellectual disability diagnoses.

The origin of these strengths and limitations is probably linked to evolutionary adaptation. Being able to focus on patterns and systems, as seen in ASD, likely helped early humans in hunting and gathering societies. They were able to respond quickly to environmental stimuli and move in an appropriate direction when they identified potential prey. A famous quote comes from the autism activist Temple Grandin, who has autism. She has said, “Some guy with high functioning Asperger's developed the first stone spear; it wasn't developed by the social ones yakking around the campfire.”

The bottom line is that appreciating and respecting neurodiversity is kind and reasonable. Another quote from Temple Grandin explains it well: “Nature is cruel, but we don't have to be.”

Prevalence rates of ASD are reported to be approximately 1% worldwide (i.e., affecting 1 in 100 people), with comparable figures observed in samples of children and adults.⁸ Prevalence estimates have increased over time and vary greatly within and across socioeconomic and demographic groups. ASD is diagnosed four times more often in males than females.²

PAUSE AND PONDER: How many symptoms of autism spectrum disorder can you list before you continue reading?

Diagnosing ASD

According to the DSM-V, diagnosis of ASD requires persistent deficits in all three areas of social communication and interaction, in addition to at least two of four types of restricted, repetitive behaviors. Table 1 lists ASD’s core characteristics and symptoms.

Table 1. Symptoms of ASD²

Social Communication Deficits

Restricted/Repetitive Behaviors

1) Deficits in social-emotional reciprocity

· Reduced sharing of interests

· Struggles with emotional recognition

2) Deficits in non-verbal communication

· Aversion to eye contact

· Abnormal body language/facial expressions

3) Deficits in developing, maintaining, and understanding relationships

· Scripted speech/taking language literally

· Difficulty in sharing imaginative play

· Difficulty making friends

· Absence of interest in peers

1) Stereotyped or repetitive motor movements, use of objects, or speech

· Arranging objects meticulously

· Echolalia (meaningless word repetition)

· Stereotypical movements like hand-flapping

2) Hypo- or hyper-reactivity to sensory input or unusual interest in sensory input

· Apparent indifference to pain/temperature

· Adverse response to sounds or textures

· Excessive smelling/touching of objects

· Visual fascination with lights or movement

3) Highly restricted, fixated interests that are abnormal in intensity or focus

· Expecting others to share their interests

· Strong attachment to unusual objects

4) Insistence on sameness, inflexibility in routines, or ritualized patterns of behavior

· Discomfort with change

Symptoms must be present in early development, cause clinically significant impairment in functioning, and cannot be attributable to intellectual disability or developmental delay. Since ASD is a spectrum, symptoms, severity, and treatment response vary widely among children and adults. Severity is categorized into three levels, described in Table 2.²

Table 2. Level of Severity of ASD²

Severity	Social Communication	Restricted/Repetitive Behaviors
Level 1 Requiring support	Noticeable impairments in social communication without support, difficulty initiating social interactions and exhibiting atypical or unsuccessful responses to social cues, possible decreased interest in social interactions Example: Able to speak full sentences, engages in communications, but social conversation attempts are odd/unsuccessful	Rigid behavior significantly disrupts functioning in various contexts, challenges transitioning between activities, difficulty with organization and planning
Level 2 Requiring substantial support	Marked deficits in verbal/nonverbal social communication skills, social impairments apparent even with support, limited initiation of social interactions, reduced/abnormal responses to social approaches from others Example: Speaks simple sentences, interaction limited to narrow special interests, odd nonverbal communication	Difficulty coping with change and showing obvious restricted/repetitive behaviors that interfere with functioning in multiple contexts, distress/difficulty switching focus
Level 3 Requiring very substantial support	Severe deficits in verbal/nonverbal social communication skills, severe impairments in functioning, very limited initiation of social interactions, minimal response to social cues from others Example: Few words of intelligible speech, rarely initiates interaction, makes unusual approaches to meet needs only and responds to only very direct social approaches	Inflexibility of behavior, extreme difficulty coping with change, restricted/repetitive behaviors significantly interfere with functioning in all contexts, great distress/difficulty changing focus or action

Prognosis

One concern for many people with ASD and their caregivers is long-term prognosis. A recent systematic review looked at data from 16 small studies (two randomized, 14 non-randomized).⁹ Only three of the included studies enrolled more than 100 participants, limiting the ability to draw conclusions, but researchers found that early intervention improved children’s prognosis considerably.

Children who received intervention before 2 years of age were more likely to improve their cognition, social skills, and stereotyped behaviors than others. They needed less monitoring at school and were better able to function and integrate socially. These researchers noted that healthcare providers often fail to offer early intervention for four reasons⁹:

Many healthcare providers are unfamiliar with the necessary screening, diagnosis, and intervention tools for ASD
Early intervention involves many different strategies and is costly
Involving parents in early intervention programs is difficult
It’s difficult to recognize ASD’s signs in toddlers younger than 2 years

ASD CASE PRESENTATION

John, a 10-year-old boy with ASD, enters the community pharmacy with his mother to pick up his prescription for aripiprazole 10 mg tablets. His agitation due to the bright lights and loud chatter from other customers becomes immediately apparent to the pharmacy team. They notice several visible signs and hear auditory cues that indicate his discomfort and distress in the environment. John's body tenses up, with rigid posture and fidgety movements, and his hands are clenched tightly as he paces and rocks back and forth. His facial expressions—furrowed brows and widened eyes—convey distress, and his vocalizations include whimpers and "I don't like it here." Additionally, John exhibits repetitive behaviors such as hand-flapping and tapping his mother. He attempts to retreat from the situation by seeking refuge behind his mother. Understanding his sensitivity to sensory input, the pharmacy team must respond with patience, empathy, and sensitivity to ensure John feels supported and safe during his visit. In addition, John’s mother will appreciate empathy and accommodation.

Strategies for Support

Pharmacists can employ their medication expertise to help the healthcare team, families, and patients improve ASD management. As John’s description indicates, patients with ASD are often sensitive to sensory input like noise, light, and crowded environments.¹⁰Pharmacists should recognize how a pharmacy setup can affect patients, potentially hindering communication. Offering to move to a quiet, dimly lit, private space (e.g., the consultation or vaccination area) for counseling helps accommodate sensory sensitivities.

When communicating with patients with ASD, pharmacists should consider the patient's level of autonomy and assess the need to interact primarily with the patient or the caregiver. Communication strategies can include using simplified language, direct communication, and patients' names to engage them and aid comprehension. Providing training to pharmacy staff on ASD can help pharmacists and technicians to serve these patients better.¹⁰

Putting Strategies in Action

The pharmacist, Keith, addresses John by name, acknowledges his discomfort, and minimizes distractions to create a more calming environment to put John at ease. For example, “Hello, John. I’m your pharmacist, and my name is Keith. It’s noisy out here. Would you like to move to a quieter room?” A technician familiar with the patient can also make this suggestion as soon as the patient arrives.

Keith also involves caregivers in the discussion, ensures they understand the medication instructions, and addresses any concerns they may have. He also reassures them of his availability for further assistance by saying, “I’m glad we talked about your medications today. If you have questions, you can stop in or call. I’m generally here Tuesday through Saturday, and my coworker Suzanne covers when I’m not here.”

By implementing these strategies, community pharmacists and technicians can improve the patient care experience for individuals with ASD.¹⁰

ASD TREATMENT

ASD is complex, and treatment often involves a multidisciplinary approach targeting various symptoms and challenges.¹¹ Although there is no outright “cure,” effective interventions may enhance functioning of children and adults with ASD. Pillars of treatment include behavioral therapies, speech and language therapy, occupational therapy, educational support, and sometimes medication management.

Behavioral therapy (e.g., applied behavioral analysis) involves creating a structured behavioral plan to improve adaptive skills and reduce inappropriate behaviors by studying affected individuals' functional difficulties systematically. Speech and language therapy is an integral part of ASD treatment for many children. Speech therapy targets difficulty with social communication and language development, which are some of ASD's core symptoms. Language therapy may employ visual supports like picture cards, augmentative and alternative communication devices, and teaching sign language (e.g., American Sign Language). Occupational therapy focuses on enhancing individuals' ability to participate in everyday activities and improve their quality of life. It typically addresses sensory processing issues, motor skill development, self-care skills, social interaction, and coping strategies, aiming to promote independence and function in various environments.¹¹

ASD treatment involves a multidisciplinary care team comprising professionals such as specialists, psychologists, pediatricians, paraprofessionals, and educators; ideally, team members collaborate to address individuals’ diverse needs and provide comprehensive support and intervention.¹¹

ASD Treatment Guidelines

Several treatment guidelines are available for ASD. The United Kingdom’s National Institute for Health and Care Excellence (NICE) has published ASD guidelines for both children under 19 years old and adults.^12,13 The Canadian Pharmacists Journal published ASD practice guidelines specifically for pharmacists. The latter guideline outlines strategies for effective communication and discusses how the community pharmacy team can create a welcoming environment for people with autism and their caregivers.¹⁰

Community pharmacists and technicians often encounter patients with diverse needs, including those with ASD. To provide optimal care, it's crucial to understand patients’ unique challenges and tailor services accordingly. Let's look at a case that highlights the importance of accommodating a patient with ASD in the pharmacy setting.

Pharmacologic Interventions

Pharmacotherapy for ASD primarily focuses on managing symptoms rather than directly targeting core features.⁸However, many challenges exist in this area, including limited efficacy and evidence, adverse effects, individual variability, lack of targeted therapies, and long-term monitoring. Prescribers should consider that children with ASD often have heightened sensitivity to medication and are more prone to adverse reactions compared to neurotypical children. It is advisable to initiate pharmacologic treatment at lower doses and increase gradually based on response and tolerability. It's crucial to gather objective symptom measures from various sources both before and after intervention to assess treatment response accurately across different settings.⁸

Another major hurdle lies in addressing co-occurring disorders that often accompany ASD, such as attention-deficit/hyperactivity disorder (ADHD), anxiety, epilepsy, sleep disorders, and more. These additional conditions complicate treatment approaches, requiring tailored interventions to address unique needs. Very limited evidence supports the effectiveness of many medications used to manage ASD symptoms.¹⁴

The lack of medications specifically targeting core ASD symptoms and the limited efficacy data for various medications present barriers to identifying effective treatment strategies. Addressing these challenges requires a comprehensive approach that integrates pharmacologic interventions with behavioral, educational, and supportive therapies personalized to the individual's specific needs and circumstances. Additionally, ongoing research is crucial to advance our understanding of ASD and to develop more effective and targeted pharmacological treatments in the future.¹⁴

Most medications for ASD are used off-label and few United States Food and Drug Administration (FDA)-approved drugs are available for specific symptom management. Medications used may include atypical antipsychotics, stimulants, serotonergic drugs, alpha-2 adrenergic antagonists, anticonvulsants, and many others.¹⁴

Atypical Antipsychotics

Prescribers often use atypical antipsychotics for irritability associated with ASD. Currently, the FDA has approved only two medications for treatment of irritability associated with ASD: risperidone and aripiprazole.^15,16 Both are atypical (second generation) antipsychotics and exert effects through dopamine, 5-HT (serotonin), alpha-adrenergic, and histaminergic receptors in the brain.

Clinical trials have demonstrated effectiveness of these drugs in reducing irritability and, to a lesser extent, repetitive behaviors. They share similar safety profiles, with common adverse effects including fatigue, increased appetite, gastrointestinal symptoms, hyperprolactinemia, weight gain, and sedation. Less common adverse effects include restlessness and akathisia (inability to remain still). Serious adverse effects such as dyslipidemia, hyperglycemia, metabolic syndrome, and extrapyramidal symptoms (e.g., involuntary movements, muscle stiffness, tremors) or drug-induced movement disorders have also been reported, necessitating close clinical and laboratory monitoring.¹⁴

Risperidone is FDA-approved for treatment of ASD-associated irritability in children and adolescents aged 5 to 16 years.¹⁵ Studies have demonstrated that risperidone may effectively improve core symptoms of ASD, including communication, social interaction, and repetitive behaviors. Non-core symptoms such as aggression, tantrums, and self-injurious behaviors also improved based on various behavioral rating scales. Risperidone is generally well-tolerated and safe, with the most common adverse effect being mild, self-limiting weight gain. In one small study of 97 children treated with risperidone over a 6-month period, participants gained an average of 5.4 kg over 24 weeks. At baseline, 59 of the 97 children (60.8%) had normal weight status. By week 24, only 25 of the remaining 85 children (29.4%) maintained normal weights.¹⁷In adults with ASD, adverse cognitive effects have not been observed in patients treated with risperidone for other psychiatric disorders. However, further exploration is needed regarding the efficacy of risperidone in adults with ASD.¹⁸

Aripiprazole is FDA-approved for treatment of ASD-associated irritability in pediatric patients 6 to 17 years old.¹⁶ Short-term studies have shown that aripiprazole can improve irritability, hyperactivity, and repetitive behaviors in children and adolescents with ASD compared to placebo. However, researchers have not observed improvement in lethargy or withdrawal symptoms. Aripiprazole use was associated with higher rates of movement disorders such as tremors and muscle rigidity. While aripiprazole may offer benefits, weight gain and neurological adverse effects like involuntary movements can limit its use. Regular monitoring of symptoms and adverse effects is recommended, and further research is needed to evaluate the long-term safety and effectiveness of aripiprazole in treating ASD.¹⁹

Other atypical antipsychotics occasionally used off-label for ASD include olanzapine, quetiapine, and ziprasidone. Providers generally avoid first generation antipsychotics due to the higher risk of movement-related adverse effects.¹⁴

Revisiting John’s Case

John's ASD is graded at Level 2—needing substantial support. He requires a range of support services tailored to his individual needs to thrive. For instance, John may benefit from behavioral interventions aimed at addressing his irritability and other behavioral challenges associated with his autism. These interventions could include strategies to manage his sensory sensitivities, develop coping skills, and enhance social communication. Additionally, providing John with structured routines and visual supports, such as clear schedules and visual cues, can help him navigate daily activities more effectively and reduce anxiety. Given his sensitivity to sensory stimuli, providing sensory accommodations like a quiet space or sensory tools (e.g., noise-canceling headphones) can aid in regulating his sensory experiences and minimizing agitation.

Moreover, John's prescription for aripiprazole indicates the need for medication management to address his irritability. Keeping in mind that John is 10 years old and in a period of rapid growth, it's crucial for the pharmacy team to monitor his height and weight regularly. The pharmacy team must inquire about any recent changes in his behavior or symptoms. The reason: the two atypical antipsychotics approved for irritability have similarities and differences that are critical to recognize, and with weight changes, the dose may require adjustments. The pharmacy team can support John's family, particularly his mother, with referral to resources such as parent training programs and support groups that can help them navigate the challenges associated with caring for a child with ASD. John can receive the assistance he needs to thrive and lead a fulfilling life with these comprehensive supports in place.

PAUSE AND PONDER: How many children with ASD receive care from your pharmacy? What behaviors do you see and hear?

Stimulants

Clinicians often prescribe stimulants to manage hyperactivity and inattention in ASD and co-existing ADHD. Two main classes of stimulants are commonly used in ADHD: amphetamines and methylphenidate derivatives.¹⁴ Prior to initiating stimulant therapy, clinicians must evaluate patients' medical and family histories and conduct a comprehensive physical exam focused on cardiovascular health. Ongoing monitoring for common adverse effects, such as appetite changes and sleep disturbances, is imperative, and it is essential to assess adolescent patients for risk of substance use or misuse before treatment initiation.

Amphetamine formulations include amphetamine-dextroamphetamine, dextroamphetamine, amphetamine sulfate, amphetamine, and lisdexamfetamine. Research suggests that amphetamines tend to be slightly more effective in reducing ADHD symptoms than methylphenidate, but they are also less tolerable. In a systematic review of data from more than 10,000 neurotypical individuals (i.e., children, adolescents, and adults without ASD), researchers found that amphetamines were more efficacious in reducing ADHD symptoms, although they were less well-tolerated than both placebo and methylphenidate in children and adolescents.²⁰

Methylphenidate products come in various formulations including immediate- and extended-release tablets or capsules, a transdermal patch, an extended-release liquid, and orally disintegrating tablets. Short-term treatment with methylphenidate has shown some benefit in improving hyperactivity, inattention, and other ADHD symptoms in children with ASD, but studies are small. The largest has enrolled just 66 children.²¹ Nonetheless, no evidence showed improvement in core ASD symptoms or social interaction. Additionally, while some children with ASD responded positively to methylphenidate, a significant number experienced adverse effects such as irritability, repetitive behaviors, insomnia, and reduced appetite.¹⁴

Alpha-2 Adrenergic Agonists

Alpha-2 adrenergic agonists—including guanfacine and clonidine—are commonly used in ADHD management for younger children. Evidence exists regarding the off-label use of alpha-2 adrenergic agonists in alleviating some symptoms of ASD, so some providers use them off label for this condition. Clinicians commonly prescribe these for children younger than 5 years old with ADHD or hyperarousal (intense, rapid, and often overwhelming emotional responses). These medications are also useful in cases when patients have poor responses to stimulants or selective norepinephrine reuptake inhibitors (e.g., atomoxetine) or when patients have significant co-occurring conditions like sleep issues that preclude stimulant use.

Research on the use of alpha-2-adrenergic agonists in ASD is limited to a few small studies.¹⁴ Guanfacine has been shown to be safe and effective in managing hyperactivity and impulsiveness in children with ASD. Common adverse effects of guanfacine include sedation, constipation, irritability, and aggression, but they are generally better tolerated than stimulant medications.¹⁴

PAUSE AND PONDER: What kinds of questions should you ask caregivers when they present a new prescription for a patient with ASD? What information do they need to know (but might not think about)?

Other Medications with Limited Supporting Data

Several medications have been explored with limited evidence in ASD management. These include various serotonergic medications (selective norepinephrine receptor inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]), anticonvulsants, gabapentin, and trazodone.

Researchers have looked at SNRIs and SSRIs to treat difficult behaviors in ASD. Venlafaxine has been proven beneficial as an adjunct treatment for self-injurious behaviors, aggression, and ADHD symptoms in children and adults with ASD, particularly when administered at doses lower than those typically used for depression.²² Conversely, duloxetine (also an SNRI) did not demonstrate any additional advantages in addressing comorbid symptoms and behaviors associated with ASD when compared to alternative antidepressants.²²

SSRIs can be helpful in patients with comorbid anxiety, which is very common with ASD. However, clinical trials assessing the SSRIs citalopram and fluoxetine found them to have low tolerability and limited effectiveness in addressing repetitive behaviors.²³

Anticonvulsants, also known as antiepileptic drugs, are sometimes used off-label in the treatment of certain ASD symptoms. While these medications are primarily indicated for seizure management, they may also be prescribed to address co-occurring conditions such as epilepsy, aggression, irritability, and repetitive behaviors in individuals with ASD. Examples of anticonvulsants studied or used in ASD treatment include valproic acid (valproate), lamotrigine, levetiracetam, and topiramate.¹⁴ However, the evidence supporting anticonvulsants' efficacy in treating ASD symptoms remains limited, and healthcare professionals should consider the use of these drugs carefully and monitor closely for potential adverse effects and individual variability in response.¹⁴

Limited research suggests that carbamazepine, oxcarbazepine, levetiracetam, and topiramate may exacerbate hyperactivity, mood disturbances, psychotic symptoms, and other psychiatric or behavioral issues in individuals with ASD.²⁴ These effects appear most common with levetiracetam. Evidence is inconclusive on the role of anticonvulsants in ASD in the absence of epilepsy, but there always remains potential for specific cases. Further research is needed to better understand the safety and effectiveness of anticonvulsants in ASD treatment and to identify subgroups of individuals who may benefit most from this approach.

Off-label use of gabapentin and trazodone for ASD presents significant patient safety concerns. Despite lacking FDA approval for this indication, these drugs are increasingly prescribed, leading to adverse drug reactions.²⁵ Gabapentin is often used off-label to address anxiety and occasionally behavioral problems. Gabapentin can also cause central nervous system depression. Its use in ASD is poorly studied, with one study that enrolled just 23 children (mean age 7.2) with various neurologic diagnoses finding that 78% of children had improved sleep at doses of 5 mg/kg 30 to 40 minutes before bedtime.²⁶ However, further research is required to substantiate these findings.²⁶

Very limited evidence supports using trazodone to manage irritability, but many individuals with ASD still use it, as sleep disturbances are very common. Safety considerations exist, as trazodone poses risks of overdose-related complications, including arrhythmias, respiratory arrest, coma, and the rare but serious condition of priapism. Overprescribing of these medications is increasing and not backed by evidence, especially in ASD. Cautious prescribing practices and thorough patient education are needed to ensure the safety and well-being of individuals with ASD using gabapentin and trazodone.

As mentioned, sleep problems are common in children with ASD. In fact, between 40% and 80% of children with ASD develop them.²⁷ For many children, insomnia is the problem, but other children develop parasomnias (e.g., sleep talking, sleepwalking, sleep terrors), or circadian rhythm sleep-wake disorders. Prescribers have various options available to treat insomnia, but in autism, the largest body of work describes the use of melatonin to improve sleep onset and maintenance. Research suggests using lowest doses (1 to 2 mg) and titrating upward gradually.^28,29

John Develops Insomnia

Once again, John and his mother visit the pharmacy to fill a prescription. His mom says that although they have a very structured schedule and John's regular bedtime is 9:00 PM, John has difficulty falling asleep and is often awake and moving around in his room for long periods of time. His mom says, “Recently, it feels like he's awake all night long and his symptoms are worse when he doesn't get enough sleep. It's a vicious cycle.” She looks exhausted; a key issue when children with ASD develop sleep disorders is that the entire family often loses sleep.

Mom also reports that her primary care provider has counseled her on ways to help John get to sleep, including discouraging behaviors that interrupt sleep, using positive reinforcement when John is actively trying to sleep, and employing relaxation techniques. She says that she moved his bedtime to 11:00 PM and he has been a little bit sleepier. Her plan is to move John’s bedtime 15 minutes earlier each week. Regardless, John and his entire family still need additional help with this issue. John’s mother indicates that the prescriber told her to speak with the pharmacist so she can find the most reliable melatonin product. That’s a prudent recommendation, since many supplements are mislabeled or unreliable.²⁸

PHARMACY IMPLICATIONS

Pharmacists, pharmacy technicians, and the community pharmacy setting serve as essential components of healthcare for patients with ASD and their families. The pharmacy team can address concerns, provide encouragement, and ensure parents and caregivers feel equipped to manage medication administration effectively. Pharmacists can provide counseling and technicians can offer support to help caregivers confidently manage medication regimens for patients with ASD, ensuring better adherence and improved healthcare outcomes. Table 3 lists important reminders for the pharmacy team.

Table 3. Best Interventions for Children with ASD at the Pharmacy^10,30,31

Anticipate that you will provide care for patients with ASD and identify a calm area where you can council without noise or distraction
Accept that some parents do not want to take any more time in a store (pharmacy or not) than they must, and try to accommodate them
At every visit, ask if anything has changed since the last visit and record an updated height and weight (especially if the patient is on a medication dosed by weight)
If parents struggle with administering medications to children with ASD
- Provide tailored support and education, offer clear and concise medication instructions using visual aids and use simplified language
- Recommend dosage forms like liquids or chewable tablets to ease administration challenges
- Offer customized packaging options such as unit-dose blister packs or pre-filled syringes proactively to simplify dosing and organization
- Help parents and caregivers create visual medication schedules or reward systems to reduce anxiety during medication administration
Encourage parents and caregivers to keep a diary of symptoms so they can monitor the patient’s response to newly prescribed medications
Remember that stimulants, gabapentin, and trazodone have been linked to abuse and all families need to be reminded to store these drugs securely
- In some states, gabapentin is a controlled substance

Pharmacists are a valuable drug information resource and adept at assessing existing evidence to help patients with ASD and their families make well-informed decisions. Pharmacy involvement is invaluable in providing optimal care and support for this patient population.

The Future of Treating ASD

The future of pharmacologic treatment for ASD holds promise but also faces significant challenges. Continued research into ASD's underlying neurobiologic mechanisms may lead to the development of more targeted interventions tailored to address specific symptoms and subtypes of the disorder. Additionally, advancements in genetic testing and biomarker identification could enable personalized treatment approaches, optimizing efficacy while minimizing adverse effects.

Large-scale clinical trials and collaborative research efforts to evaluate treatment effectiveness comprehensively are needed. Ultimately, the future of medication therapy for ASD will depend on the ability to integrate advancements with a nuanced understanding of individual differences and needs of patients with ASD.¹⁴

CONCLUSION

While progress has been made in understanding and treating ASD, significant challenges remain. A comprehensive approach combining behavioral interventions, therapies, and pharmacotherapy tailored to individual needs is essential for improving outcomes in individuals with ASD. Continued research efforts are necessary to develop more effective and evidence-based treatments for this complex disorder. Temple Grandin explains it well: “A treatment method or an educational method that will work for one child may not work for another child. The one common denominator for all of the young children is that early intervention does work, and it seems to improve the prognosis.”

UNDERSTANDING TREATMENT APPROACHES FOR AUTISM SPECTRUM DISORDER

Pharmacist Post Test

After completing this continuing education activity, pharmacists will be able to
• DESCRIBE autism spectrum disorder (ASD) and its manifestations
• LIST medications used to manage symptoms of ASD
• APPLY techniques to improve care in the pharmacy for patients with ASD and their caretakers

1. Which of the following is TRUE about autism spectrum disorder?
A. It affects 10% of children worldwide
B. It affects four times as many males than females
C. Prevalence has decreased over the past decade

2. Which of the following symptom lists BEST represents autism spectrum disorder?
A. Avoiding eye contact, sensitivity to loud noises, disinterest in peers or making friends
B. Strong attachment to unusual objects, sensitivity to cold temperatures, discomfort with change
C. Hand flapping, excessive smelling of objects, increased sharing of imaginative play

3. Which job would an individual with ASD be expected to excel at?
A. A professional musician
B. A manufacturing job in a busy warehouse
C. An accounting job at a quiet firm

4. Which of the following is TRUE about sleep disorders in patients with ASD?
A. They are relatively uncommon, affecting about 20% of patients with ASD
B. They are best treated with non-pharmacologic techniques with or without melatonin
C. Patients with ASD typically only develop parasomnias like sleepwalking or sleep talking

5. Which of the following is FDA-approved to treat ASD-associated irritability in a 5-year-old?
A. Quetiapine
B. Aripiprazole
C. Risperidone

6. Which of the following is TRUE about aripiprazole for ASD?
A. It’s used off-label to treat ASD-associated insomnia
B. It can improve repetitive behaviors seen in ASD
C. It’s known to cause decreased appetite and weight loss

7. Which of the following co-occurring conditions in a patient with ASD could benefit from the use of dextroamphetamine?
A. Attention-deficit/hyperactivity disorder
B. Sleep disturbances (e.g., insomnia)
C. Self-injurious behaviors and aggression

8. Which of the following is gabapentin used off-label to treat in ASD?
A. Insomnia
B. Anxiety
C. Epilepsy

9. George is a 3-year-old boy who comes to the pharmacy with his mom. George’s mom asks your help picking out a melatonin supplement for her son who is having trouble sleeping at night. She explains that his pediatrician recommended getting him evaluated for ASD based on other symptoms he is exhibiting, but she thinks this isn’t necessary. She says “he’s just a toddler who can’t sleep because he’s too excited, we’ll try the melatonin first.” Which of the following is the BEST response?
A. Advocate to have George evaluated soon, rather than waiting, as outcomes are better for patients who are diagnosed and treated earlier
B. Let her know she’s right to delay evaluation because providers typically can’t diagnose ASD before 8 years of age
C. Offer to contact George’s pediatrician to see if she is willing to prescribe trazodone, as it works better for patients with ASD-associated insomnia

10. Amelia is a 12-year-old patient with diagnosed ASD who comes to the pharmacy with her mom to pick up her prescription for aripiprazole. You are understaffed due to a call out and the only technician is assisting someone in the drive thru while you are on hold with an insurance company. Amelia and her mom are third in line at pick-up, and you notice Amelia is pacing back and forth, shielding her eyes from the fluorescent lights, and tugging her mom’s arm asking to leave. Which of the following is the BEST course of action?
A. Toss Amelia’s mom your noise-cancelling headphones and a pair of sunglasses and tell her you will be with her as soon as you can
B. Make a note to contact Amelia’s provider and let them know that her aripiprazole dose should be increased
C. Offer to let Amelia and her mom wait in your vaccination area with the lights off until you or the technician can help her

UNDERSTANDING TREATMENT APPROACHES FOR AUTISM SPECTRUM DISORDER

Pharmacy Technician Post-test

After completing this continuing education activity, pharmacy technician will be able to
• DESCRIBE autism spectrum disorder (ASD) and its manifestations
• LIST medications used to manage symptoms of ASD
• RECOGNIZE situations in which they can help patients with ASD and their caretakers appropriately

3. Which job would an individual with ASD be expected to excel at?
A. A professional musician
B. A manufacturing job in a busy warehouse
C. An accounting job at a quiet firm

5. Which of the following is FDA-approved to treat ASD-associated irritability in a 5-year-old?
A. Quetiapine
B. Aripiprazole
C. Risperidone

8. Which of the following is gabapentin used off-label to treat in ASD?
A. Insomnia
B. Anxiety
C. Epilepsy

9. Which of the following strategies helps patients with ASD feel more comfortable coming to the pharmacy?
A. Greet them by name upon arrival
B. Avoid talking to them directly
C. Conduct transactions as slowly as possible

10. Amelia is a 12-year-old patient with diagnosed ASD who comes to the pharmacy with her mom to pick up her prescription for aripiprazole. You are understaffed due to a call out and you are the only technician working today. You are assisting someone in the drive thru while the pharmacist is on hold with an insurance company. Amelia and her mom are third in line at pick-up, and you notice Amelia is pacing back and forth, shielding her eyes from the fluorescent lights, and tugging her mom’s arm asking to leave. Which of the following is the BEST course of action?
A. Toss Amelia’s mom your noise-cancelling headphones and a pair of sunglasses and tell her you will be with her as soon as you can
B. Make a note to tell the pharmacist to contact Amelia’s provider and let them know that her aripiprazole dose should be increased
C. Offer to let Amelia and her mom wait in your vaccination area with the lights off until you or the pharmacist can help her

References

1. Sasson NJ, Pinkham AE, Carpenter KL, Belger A. The benefit of directly comparing autism and schizophrenia for revealing mechanisms of social cognitive impairment. J Neurodev Disord. 2011;3(2):87-100. doi:10.1007/s11689-010-9068-x
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). 2022;5(5). https://doi.org/10.1176/appi.books.9780890425787
3. Keating CT, Hickman L, Leung J, et al. Autism-related language preferences of English-speaking individuals across the globe: A mixed methods investigation. Autism Res. 2023;16(2):406-428. doi:10.1002/aur.2864
4. Bąbel P, Ostaszewski P. Between neurodiversity and therapy: the importance of making conscious and responsible choices in supporting individuals on the autism spectrum. Postep Psychiatr Neurol. 2023;32(4):175-180. doi:10.5114/ppn.2023.135596
5. Armstrong T. The myth of the normal brain: embracing neurodiversity. AMA J Ethics. 2015;17(4):348-352. doi:10.1001/journalofethics.2015.17.4.msoc1-1504
6. Brüne M, Belsky J, Fabrega H, et al. The crisis of psychiatry - insights and prospects from evolutionary theory. World Psychiatry. 2012;11(1):55-57. doi:10.1016/j.wpsyc.2012.01.009
7. Solomon A. The autism rights movement. New York Magazine. June 2, 2008. Accessed April 4, 2024. http://nymag.com/news/features/47225/
8. Zeidan J, Fombonne E, Scorah J, et al. Global prevalence of autism: A systematic review update. Autism Res. 2022;15(5):778-790. doi:10.1002/aur.2696
9. Pires JF, Grattão CC, Gomes RMR. The challenges for early intervention and its effects on the prognosis of autism spectrum disorder: a systematic review. Dement Neuropsychol. 2024;18:e20230034. doi:10.1590/1980-5764-DN-2023-0034
10. Kadi R, Gayed F, Kauzman P, et al. Autism spectrum disorder: Practice guidelines for pharmacists. Can Pharm J (Ott). 2024;157(2):58-65. doi:10.1177/17151635241228495
11. Hyman SL, Levy SE, Myers SM; COUNCIL ON CHILDREN WITH DISABILITIES, SECTION ON DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020;145(1):e20193447. doi:10.1542/peds.2019-3447
12. Autism spectrum disorder in under 19s: support and management. London: National Institute for Health and Care Excellence (NICE); June 14, 2021.
13. Autism spectrum disorder in adults: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); June 14, 2021.
14. Aishworiya R, Valica T, Hagerman R, Restrepo B. An Update on Psychopharmacological Treatment of Autism Spectrum Disorder. Neurotherapeutics. 2022;19(1):248-262. doi:10.1007/s13311-022-01183-1
15. Risperdal [package insert]. Janssen Pharmaceutical Companies; 2022. Accessed May 10, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020272s087,021444s059lbl.pdf
16. Abilify [package insert]. Otsuka Pharmaceutical Co; 2022. Accessed May 10, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021436s048lbledit.pdf
17. Scahill L, Jeon S, Boorin SJ, et al. Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2016;55(5):415-423. doi:10.1016/j.jaac.2016.02.016
18. Hutchinson J, Folawemi O, Bittla P, et al. The Effects of Risperidone on Cognition in People With Autism Spectrum Disorder: A Systematic Review. Cureus. 2023;15(9):e45524. doi:10.7759/cureus.45524
19. Hirsch LE, Pringsheim T. Aripiprazole for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2016;2016(6):CD009043. doi:10.1002/14651858.CD009043.pub3
20. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-738. doi:10.1016/S2215-0366(18)30269-4
21. Posey DJ, Aman MG, McCracken JT, et al. Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures. Biol Psychiatry. 2007;61(4):538-544. doi:10.1016/j.biopsych.2006.09.028
22. Nanjappa MS, Voyiaziakis E, Pradhan B, Mannekote Thippaiah S. Use of selective serotonin and norepinephrine reuptake inhibitors (SNRIs) in the treatment of autism spectrum disorder (ASD), comorbid psychiatric disorders and ASD-associated symptoms: a clinical review. CNS Spectr. 2022;27(3):290-297. doi:10.1017/S109285292000214X
23. Hellings J. Pharmacotherapy in autism spectrum disorders, including promising older drugs warranting trials. World J Psychiatry. 2023;13(6):262-277. doi:10.5498/wjp.v13.i6.262
24. Chen B, Choi H, Hirsch LJ, et al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017;76:24-31. doi:10.1016/j.yebeh.2017.08.039
25. Lenzer J. Pfizer pleads guilty, but drug sales continue to soar. BMJ. 2004;328(7450):1217. doi:10.1136/bmj.328.7450.1217
26. Mammarella V, Orecchio S, Cameli N, et al. Using pharmacotherapy to address sleep disturbances in autism spectrum disorders. Expert Rev Neurother. 2023;23(12):1261-1276. doi:10.1080/14737175.2023.2267761
27. Sidhu N, Wong Z, Bennett AE, Souders MC. Sleep Problems in Autism Spectrum Disorder. Pediatr Clin North Am. 2024;71(2):253-268. doi:10.1016/j.pcl.2024.01.006
28. Souders MC, Taylor BJ, Zavodny Jackson S. Sleep Problems in Autism Spectrum Disorder. In: White SW, Maddox BB, Mazefsky CA, eds. The Oxford Handbook of Autism and Co-Occurring Psychiatric Conditions. Oxford University Press; 2020: 258-283. Accessed May 10, 2024. https://academic.oup.com/edited-volume/28150/chapter-abstract/212932907
29. Williams Buckley A, Hirtz D, Oskoui M, et al. Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2020;94(9):392-404. doi:10.1212/WNL.0000000000009033
30. Kurtz SP, Buttram ME, Margolin ZR, Wogenstahl K. The diversion of nonscheduled psychoactive prescription medications in the United States, 2002 to 2017. Pharmacoepidemiol Drug Saf. 2019;28(5):700-706. doi:10.1002/pds.4771
31. Anderson LA. Is gabapentin a controlled substance/narcotic? Drugs.com. Updated December 5, 2022. Accessed April 5, 2024. https://www.drugs.com/medical-answers/gabapentin-narcotic-controlled-substance-3555993/

Demystifying the Medicare Prescription Payment Plan

After completing this application-based continuing education activity, pharmacists and technicians will be able to

Describe the benefits and features of the Medicare Prescription Payment Plan
Outline the responsibilities of Part D Sponsors and dispensing pharmacies under the Medicare Prescription Payment Plan
Discuss the characteristics of beneficiaries most likely to benefit from participating in the Medicare Prescription Payment Plan
Explain the resources available for Medicare Beneficiaries to learn more about the Medicare Prescription Payment Plan

More than 1.4 million Americans paid drug costs of $2000 or more in 2020. Starting January 1, 2025, the M3P allows Medicare Part D members the option to pay for their Part D medications through a monthly invoice while paying nothing at the pharmacy counter. This change has operational and financial impacts for many areas of pharmacy. M3P claims processing requires coordination between Plans, PBMs, and dispensing pharmacies. Pharmacists and pharmacy technicians can help their patients benefit from the M3P by educating themselves and their patients about the program.

INTRODUCTION & BACKGROUND

The Inflation Reduction Act (IRA) of 2022 is a large piece of legislation that included a wide range of provisions, including clean energy, tax revenues, and healthcare costs. The Medicare Part D changes contained in the IRA aim to make prescription drugs more affordable for Medicare beneficiaries.¹

One of the Medicare Part D changes included in the IRA is the Medicare Prescription Payment Plan (M3P). Starting January 1, 2025, the M3P allows Medicare Part D members the option to pay for their Part D medications through a monthly invoice while paying nothing at the pharmacy counter.² This change has operational and financial impacts for many areas of pharmacy, including dispensing pharmacies, Medicare Part D Plans (Plans), and Pharmacy Benefit Managers (PBMs).

Overview of the Medicare Prescription Payment Plan

The Kaiser Family Foundation estimated that more than 1.4 million Americans paid drug costs of $2000 or more in 2020.³ While the IRA contains other provisions designed to lower prescription drug costs, the M3P does not change the amount that patients pay for their medications. Instead, the M3P (originally called “copay smoothing”) helps Medicare beneficiaries afford their prescriptions by “smoothing” the costs over monthly invoices instead of paying the full amount to their pharmacy. The IRA requires Plans to make the M3P available to any member who has out-of-pocket costs for Part D medications, regardless of their income or out-of-pocket amount. The M3P also requires Plans to⁴

Educate members about the availability of the M3P
Notify dispensing pharmacies when members are likely to benefit from participating in the M3P
Reflect $0 member payment for approved M3P claims
Allow multiple methods for members to opt-in to the M3P
Issue monthly M3P invoices to participating members
Include all prescriptions covered under Medicare Part D in the M3P
Pay the dispensing pharmacy for the member’s portion of the drug cost

Figure 1 illustrates the basic process for patients who choose to participate in M3P.

The Centers for Medicare & Medicaid Services (CMS) requires Plans to educate members about the availability of M3P through a variety of channels. Plans must include general M3P information on their websites, when issuing new member identification, and with annual plan document mailings. Plans and dispensing pharmacies must also provide M3P information to targeted members who are likely to benefit from participating in the program. CMS has determined that members with out-of-pocket costs of at least $2000 in the first three quarters of the year or $600 for a single prescription are the most likely to benefit from using the M3P.⁵

M3P claims processing starts January 1, 2025, and requires coordination between Plans, PBMs, and dispensing pharmacies. For members not participating in the M3P, Plans, through their PBMs, must indicate that the patient is likely to benefit from the M3P on approved Part D prescription claims with patient costs that are $600 or more. Receipt of this information from the claim requires the dispensing pharmacy to provide educational materials about the M3P to the patient. While CMS requires pharmacies to distribute M3P information to patients in response to claims messaging, CMS does not require them to provide additional counseling about the program. Pharmacists and pharmacy technicians may, however, choose to educate themselves and their patients about the M3P to provide an elevated patient experience.⁵

PAUSE AND PONDER: What quick talking points can you provide to your patients to help them understand the M3P?

Approved Part D claims for patients who have opted into the program will include instructions for the dispensing pharmacy to send a secondary M3P claim. The secondary M3P claim must use a different Bank Identification Number/Processor Control Number (which pharmacy staff usually refer to as BIN/PCN) combination than the corresponding primary Part D claim. The National Council for Prescription Drug Programs (NCPDP) creates and maintains the standardized format for prescription claims transmission. NCPDP is adding specific transmission codes for PBMs to transmit M3P information to dispensing pharmacies.⁴ Table 1 describes the types of M3P claims processing information that dispensing pharmacies should expect starting January 1, 2025. Pharmacists and technicians should consult their employer’s training materials for specific instructions on providing patients with information about the M3P, using NCPDP M3P transmission codes, and submitting secondary M3P claims.

Table 1. Anticipated M3P Claims Messaging Information

Patient Status	Claim Type	Message Type
Not participating in M3P	Approved Part D Claims with ≥ $600 patient cost	The member is likely to benefit from participating in the M3P; the pharmacy should provide M3P educational information.
Not participating in M3P	Secondary M3P Claims (if sent accidentally)	The member is not participating in the M3P program; the pharmacy should collect the member’s cost share based on the Part D claim.
Participating in M3P	Approved Part D Claims	The member is participating in the M3P; the pharmacy should send a secondary M3P claim.
Participating in M3P	Secondary M3P Claims	The corresponding Part D claim is not found. Transmission may have failed or the Part D claim has been reversed; the pharmacy should reprocess the Part D claim and then re-send the secondary M3P claim.
Participating in M3P	Secondary M3P Claims	The drug is not covered by Part D and therefore not eligible for M3P; the pharmacy should collect the member’s cost share based on the Part D claim.

Members can start signing up for the M3P as early as October 15, 2024, which is the beginning of open enrollment for 2025 Medicare Part D coverage. They can also sign up any time after their 2025 Part D coverage starts. CMS requires Plans to accept M3P participation requests by mail, telephone, or through a website application.⁴ CMS does not currently require dispensing pharmacies to process M3P election requests, and pharmacists and pharmacy technicians should direct patients to their Plan to sign up for the M3P.

Once a member opts into the program, their Plan will issue a monthly M3P invoice for all Part D prescription costs including the deductible and copay/coinsurance amounts. CMS requires Plans to issue M3P invoices separately from monthly premium invoices.⁴

Plans can remove members from M3P participation for failure to pay M3P invoices after a 2-month grace period but cannot disenroll members from Part D coverage for failure to pay M3P invoices. Members who are removed from M3P participation for falling behind on M3P payments can restore their M3P participation by paying their past-due M3P balance in full.⁴ Plans may disenroll members from Part D coverage for failure to pay monthly premium invoices after a 2-month grace period, even if their M3P invoices are paid in full.⁶ Pharmacists and pharmacy technicians can help M3P patients stay current with their payments by reminding them to pay both M3P and monthly Part D premium invoices. The SIDEBAR explains common terms.

SIDEBAR: Part D Patient Costs Defined

Monthly Premium: a monthly payment that maintains enrollment in the Plan; not impacted by deductible, copay, or coinsurance amounts

Annual Deductible: a yearly dollar amount the patient pays before their Plan starts to contribute to prescription costs

Copayment (or Copay): a specific, pre-determined dollar amount the patient pays for each prescription after satisfying the deductible

Coinsurance: an alternative to a copay, the percentage of the total cost the patient pays for each prescription after satisfying the deductible

Distribution of M3P responsibilities

CMS develops guidance and member-facing documents that Plans and PBMs use when building operational processes. For the M3P, CMS is providing Plans with⁵

Detailed guidance documents that provide M3P requirements and invoice calculation instructions
Content for plan mailings including the Annual Notice of Change, Evidence of Coverage, and Explanation of Benefits
A fact sheet with educational language for Plan websites and printed materials
An election request form
Letters to notify members of M3P election, failure to pay, and termination from the program
A targeted letter for members who are likely to benefit from participating in the M3P

CMS is also adding M3P information to the resources and educational materials that they provide directly to Medicare beneficiaries, including the annual Medicare & You Handbook, Medicare.gov, and Medicare Plan Finder.⁵

CMS assigns most of the responsibility for the M3P to Plans and holds Plans accountable for meeting all program requirements. Plans are responsible for delivering all aspects of the M3P but must rely on PBMs, vendors, and dispensing pharmacies for certain requirements. Table 2 provides an overview of the main activities that Plans must implement for M3P.^4,5

Table 2. Plan M3P Responsibilities^{4, 5}

Activity	Requirements
Member education	· General information during open enrollment, with annual plan mailings, and on their website · Targeted information prior to and during the plan year for members who are likely to benefit from the M3P
M3P participation processing	· Mail, telephone, and web-based options · Accept M3P elections during open enrollment, before the start of the plan year · Activate completed M3P elections received during the plan year within 24 hours · Outreach to gather missing information from incomplete M3P election requests · Communication to PBM for claims processing
M3P claims processing	· Coordination and oversight of their PBM for o Claims notification to pharmacies for members who are likely to benefit from M3P o Processing information and $0 copay/coinsurance for M3P participants o Payment to the dispensing pharmacy for the member’s portion of the drug cost
M3P Invoices and Payment Collections	· Monthly invoices based on CMS-required calculations · 60-day grace period, then removal from M3P for failure to pay
Other	· Customer service · Pharmacy and provider education · Data and reporting · Oversight of dispensing pharmacies

While Plans hold the most responsibility for M3P, dispensing pharmacies play a large part in the program’s success. CMS requires all pharmacies who accept Part D prescription drug coverage to participate in the M3P. Pharmacists and pharmacy technicians must act on M3P claim information to distribute M3P materials to members and process M3P claims.Pharmacies may need to adjust their claim reversals and reprocessing procedures to ensure that both the primary Part D and the secondary M3P claims are included. For example, if a patient decides to fill a prescription for less than the original quantity, the pharmacy would need to first reverse both the Part D and M3P claims and then resubmit both claims with the new quantity. CMS also requires pharmacies to re-process claims for members who sign up for M3P after filling but before picking up their prescriptions.^4,5

To benefit from the M3P, Medicare beneficiaries are responsible for reviewing the educational materials provided by CMS, their Plan, and their pharmacy. They also have the opportunity to use the tools provided by their Plan to determine if they would benefit from participating in the M3P. After signing up, members are obligated to pay their M3P invoices on a monthly basis to avoid being removed from the program. Members who sign up for the M3P may decide later to drop out of the program but are still responsible for paying invoices incurred during their M3P participation.^4,5

Monthly invoice calculations and members most likely to benefit from participating in the M3P

The monthly invoice calculations required by CMS are complex and typically do not result in equal monthly installments. Members can sign up for the M3P at any time during the year, and the monthly invoice calculation for their first month in the program is different from the invoice calculations for later months. Invoice amounts also vary based on when the member signs up for the M3P and prescriptions purchased at the pharmacy before they entered the program. CMS protects members who participate in the M3P by prohibiting Plans from adding service/late fees or charging interest on M3P balances.⁴

PAUSE AND PONDER: What can you tell a patient who asks how the M3P is different than using a credit card to pay for his prescriptions?

CMS holds Plans responsible for accurately calculating M3P invoice amounts and answering member questions. Dispensing pharmacies are not required to explain invoice details but may benefit from understanding why not all patients will benefit from participating in the M3P.⁴

Figures 2 and 3 provide examples of pharmacy copay/coinsurance amounts compared to M3P invoice amounts for members who sign up for M3P in January. Both example members have the same out-of-pocket prescription costs for the year. The member in Figure 2 is more likely to benefit financially from the M3P because the monthly M3P invoice amount is never higher than what they would have paid at the pharmacy counter. In general, the higher the member’s out-of-pocket prescription costs the earlier in the year, the more likely the member will benefit financially from using the M3P.⁴

All Part D members are entitled to sign up for the M3P, regardless of their drug costs or M3P invoice amounts. Members who do not benefit financially from the M3P, such as the member illustrated in Figure 3, may have personal reasons for signing up for the program. For example, patients who rely on caretakers to pick up their prescriptions from the pharmacy may prefer the convenience of having no cost at the pharmacy counter. Patients may also pay more than their MP3 invoice amounts earlier in the year to reduce invoice amounts later in the year as long as they do not pay more than their total year-to-date copay/coinsurance amounts.⁴

Alternatively, patients may have non-financial reasons for not signing up for the M3P. They may not want to receive another monthly bill or may feel that paying for their prescriptions at the pharmacy provides better visibility into their drug costs. Even patients who would benefit financially from using the M3P may be put off by the uneven monthly M3P payment amounts. Patients who sign up for the M3P have the option to leave at any time if they feel they are not benefiting from the program.

PAUSE AND PONDER: What other non-financial situations may members face where they could benefit from the M3P?

M3P Resources

CMS has a number of resources available for anyone looking for more information about the M3P. They provide access to detailed M3P guidance, technical, and related information at https://www.cms.gov/inflation-reduction-act-and-medicare/part-d-improvements/medicare-prescription-payment-plan

CMS also provides an annual handbook entitled “Medicare and You” designed to educate members about all aspects of Medicare. When the 2025 version of “Medicare and You” is released by CMS in late 2024, it will include educational information about the M3P.⁵ The “Medicare and You” handbook is available at https://www.medicare.gov/medicare-and-you.

At the time of this publication, CMS is still developing additional resources, but expects information about the M3P to be available at www.medicare.gov.⁵

CMS requires Plans to provide information about the M3P on their websites before October 15, 2024. While the general M3P information included on Plan websites will likely be similar to the information provided by CMS, it will also include Plan-specific instructions and contact information.⁵

SUMMARY AND CONCLUSION

The M3P provides flexibility for Medicare beneficiaries who prefer to receive a monthly invoice instead of paying for their prescriptions at the pharmacy counter. The program requires complex operational changes for Plans, PBMs, and dispensing pharmacies.

CMS holds Plans responsible for the overall administration of the M3P, but PBMs and dispensing pharmacies have important responsibilities. Pharmacists and pharmacy technicians can help their patients benefit from the M3P by educating themselves and their patients about the program.

Good:

Be familiar with your pharmacy’s procedures for processing M3P claims
Provide M3P information to patients when prompted by your pharmacy’s dispensing system
Refer patients to their Plan for additional information about the M3P

Better:

Discuss the overall benefits of the M3P
Answer patient questions about how the M3P works
Describe the characteristics of patients most likely to benefit from using the M3P

Best:

BE COMMUNITY CHAMPIONS! Stay abreast of upcoming changes and take the time to comment on proposed revisions to Medicare
Assist patients with decisions about M3P participation
Consider appointing one staff member to be your “M3P Expert” who deals with complex patient questions

Demystifying the Medicare Prescription Payment Plan
Educational Objectives for Pharmacists and Pharmacy Technicians:
1. Describe the benefits and features of the Medicare Prescription Payment Plan
2. Outline the responsibilities of Part D Sponsors and dispensing pharmacies under the Medicare Prescription Payment Plan
3. Discuss the characteristics of beneficiaries most likely to benefit from participating in the Medicare Prescription Payment Plan
4. Explain the resources available for Medicare Beneficiaries to learn more about the Medicare Prescription Payment Plan.

1. What can you tell patients who ask about the Medicare Prescription Payment Plan?
a. It will lower prescription drug costs for millions of Americans
b. It creates an option to pay for Part D prescriptions through a monthly invoice
c. The government will make this program available on January 1, 2026

2. What can members who participate in the Medicare Prescription Payment Plan expect?
a. They will pay $0 at the pharmacy for their Part D prescriptions
b. They must meet strict minimum income requirements
c. They will receive monthly invoices from their pharmacy

3. Which of the following is an M3P responsibility for dispensing pharmacies?
a. Provide counseling about the program
b. Distribute materials in response to claims messaging
c. Identify patients who are likely to benefit from the program

4. If a member fails to pay M3P invoices, what could happen?
a. They could be required to change pharmacies
b. They could be denied prescription drug coverage
c. They could be removed from the M3P program

5. Which of the following is a Medicare Part D Plan responsibility?
a. Processing M3P participation requests
b. Allowing a 90-day grace period for failure to pay M3P invoices
c. Developing guidance and member-facing documents

6. Which Medicare beneficiaries are most likely to benefit financially from using the M3P?
a. People who have high drug costs early in the year
b. People who have low drug costs throughout the year
c. People who have high drug costs late in the year

7. What advice can you offer to patients who do not benefit financially from the M3P?
a. They are not permitted to use the program
b. They must remain in the program until the end of the plan year
c. They may choose to join the program for non-financial reasons

8. Which of the following may patients consider a disadvantage to using the M3P, even for patients who may benefit financially from the program?
a. Invoice amounts that are not the same every month
b. Being required to change pharmacies to participate
c. Risk of losing their prescription coverage if they cannot pay their M3P invoices

9. Where can beneficiaries learn more about the M3P?
a. The 2024 “Medicare and You” Handbook
b. From their Plan Formulary
c. CMS and Plan websites

10. When will Medicare Part D Plans have M3P details available on their websites and start accepting M3P member elections?
a. After patients meet their annual deductible
b. No later than October 15, 2024
c. After January 1, 2025

References

Centers for Medicare & Medicaid Services. The Inflation Reduction Act Lowers Health Care Costs for Millions of Americans. Accessed April 27, 2024. https://www.cms.gov/priorities/legislation/inflation-reduction-act-and-medicare/lowers-health-care-costs-millions-americans

Centers for Medicare & Medicaid Services. Fact Sheet: Medicare Prescription Payment Plan. Accessed April 27, 2024. https://www.cms.gov/files/document/medicare-prescription-payment-plan-fact-sheet.pdf

Kaiser Family Foundation. Explaining the Prescription Drug Provisions in the Inflation Reduction Act. Accessed July 1, 2024. https://www.kff.org/medicare/issue-brief/explaining-the-prescription-drug-provisions-in-the-inflation-reduction-act/
Centers for Medicare & Medicaid Services. Medicare Prescription Payment Plan: Final Part One Guidance on Select Topics, Implementation of Section 1860D-2 of the Social Security Act for 2025, and Response to Relevant Comments. Accessed April 27, 2024. https://www.cms.gov/files/document/medicare-prescription-payment-plan-final-part-one-guidance.pdf

Centers for Medicare & Medicaid Services. Medicare Prescription Payment Plan: Final Part Two Guidance on Select Topics, Implementation of Section 1860D-2 of the Social Security Act for 2025, and Solicitation of Comments. Accessed July 17, 2024. https://www.cms.gov/files/document/medicare-prescription-payment-plan-final-part-two-guidance.pdf

Centers for Medicare & Medicaid Services. What Happens When a Plan Member Doesn’t Pay Their Medicare Plan Premiums? Accessed April 28, 2024. https://www.cms.gov/outreach-and-education/outreach/partnerships/downloads/11338-p.pdf

Management of Adults with Type 2 Diabetes: A Patient-Focused Approach

After completing this application-based continuing education activity, pharmacists will be able to

· Describe type 2 diabetes diagnostic criteria and glycemic targets

· Identify the components of diabetes self-management education and support

· Recognize the importance of an individualized treatment program

· List treatment recommendations for type 2 diabetes in the setting of common comorbidities

After completing this application-based continuing education activity, pharmacy technicians will be able to

· Describe type 2 diabetes diagnostic criteria and glycemic targets

· Identify the components of diabetes self-management education and support

· Recognize the importance of an individualized treatment program

· List common comorbidities in type 2 diabetes

The diabetes epidemic is growing globally. Knowledge of current standards of care is essential for healthcare professionals. Understanding the importance of lifestyle recommendations and current pharmacologic therapies based on comorbidities is integral to improving diabetic patient outcomes. This continuing education activity follows a format similar to the Standards of Medical Care in Diabetes, focusing on the non-pregnant adult with T2DM. The current standards stress the importance of assessing each patient as an individual and emphasize a team care approach with patient involvement in monitoring diet, weight, physical exercise, and glycemic targets. This continuing education activity reviews the treatment of comorbid conditions, including obesity, hyperlipidemia, hypertension, heart disease, and chronic kidney disease, in addition to glycemic care. Using glucose-lowering therapy that decreases weight and slows cardiovascular disease progression is the new standard of care. Current medication therapy highlights incorporation of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 agonists into therapeutic treatment plans.

INTRODUCTION

Many years ago, I dined with a large man who looked as if he had lost a substantial amount of weight. He ordered meat and vegetables and explained to me that he had eliminated most carbohydrates from his diet. As a result of dietary changes, he was able to discontinue his diabetes medication. As a pharmacist, this concept of treating a disease with lifestyle changes, rather than medication, left a profound impact.

Globally, diabetes mellites is the ninth major cause of death. This epidemic has quadrupled in the past 30 years, affecting about one in 11 adults.¹ Type 2 diabetes mellitus (T2DM) accounts for approximately 90% of diabetes mellitus diagnoses.¹ Traditionally, treatment goals focused on hemoglobin A1C (HbA1c) and blood glucose levels to treat T2DM. However, the incidence of diabetes and diabetic complications continues to rise despite the many hypoglycemic medications on the market.^2,3 Many older hypoglycemics can lead to weight gain, conflicting with the treatment goal of decreasing body mass.⁴ Optimizing diet, nutrition, and physical exercise are important treatment components, but patients may find this challenging. The healthcare team can supply the necessary support to optimize therapy. If lifestyle modifications and traditional treatments are ineffective, newer T2DM medications offer novel treatment approaches that potentially improve overall patient outcomes.

Prevalence and Risk Factors

The global adult prevalence of diabetes is significant and varies by several factors⁵:

Overall, approximately 6.1%
Males 6.5%
Females 5.8%
Older adults between the ages of 65 and 95 years, over 20%
Adults in their late 70’s (75 to 79 years) 24.4%.

In 76.5% of those with T2DM, research found risk factors were present, with high body mass index (BMI) being the primary risk factor for T2DM worldwide. Other risk factors included dietary risks, environmental or occupational risks, tobacco use, low physical activity, and alcohol use.⁵

According to the Centers for Disease Control and Prevention (CDC) National Diabetes Statistics Report (2023), in the United States in 2019, 8.7% of the population had diagnosed diabetes. Its prevalence also varied by ethnicity⁶:

Native Americans and Alaska Natives 14.5%
Non-Hispanic blacks 12.1%
Hispanics 11.8%
Non-Hispanic Asians 9.5%
Non-Hispanic whites 7.4%.

People with less than a high school education were more likely to have diabetes (13.4%) than those with a high school education (9.2%) and those with more than a high school education (7.1%). Below the federal poverty level, the prevalence was 13.7% for men and 14.4% for women. The percentages vary depending on the affected individuals’ eating and exercise habits, age, ethnicity, culture, location, education level, and economic status.⁶

Diagnosis

According to the American Diabetes Association (ADA) Professional Practice Committee Classification and Diagnosis of Diabetes, clinicians diagnose T2DM according to one of the following criteria⁷:

A fasting plasma glucose level of 126 mg/dL (7 mmol/L) or higher
A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-gram oral glucose tolerance test
A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis
A HbA1c level of 6.5% (48 mmol/mol) or higher.

Glycemic Goals

Clinicians in all walks of practice use guidelines to monitor glycemic status in patients with diabetes. Assessing glycemic status at least two times annually in patients who have stable glycemic control is sufficient. Assessment of glycemic status involves one or more of the following⁸:

Monitoring HbA1c status
Employing a continuous glucose monitoring device with time in range monitoring
Using a device containing a glucose management indicator.

The ADA recommends quarterly HbA1c monitoring for those with less stable glycemic control.^8,9 The HbA1c goal for most nonpregnant adults is 7% if the patient experiences no significant hypoglycemia. If the patient uses ambulatory glucose management, a target goal of 6.5% may be suitable. Less stringent HbA1c goals of up to 8% may be appropriate for patients with limited life expectancy or if treatment harm outweighs its benefits. When patients experience unexplained hypoglycemia, providing prompt hypoglycemia avoidance education or raising the glycemic targets are essential interventions, especially in patients with low cognition or declining cognition.⁹

COMMON COMORBIDITIES

Frequently, patients with T2DM have comorbidities. A review study analyzed patients with T2DM at varying times from diagnosis to identify the dominant multimorbidity cluster types. The study found that three condition clusters appeared consistently^10-13:

Cardiometabolic precursor conditions are common at diagnosis of T2DM
- Disorders of lipid metabolism (hyperlipidemia)
- Obesity
- Hypertension

Vascular conditions are usually associated with later stage T2DM
- Coronary artery disease (which can lead to heart failure)
- Chronic kidney disease
- Peripheral vascular disease (including peripheral arterial disease)
- Stroke (a manifestation of cerebrovascular disease)
- Atrial fibrillation

Mental health conditions occur regardless of diabetes duration
- Depression (the second most common condition in females after hypertension)
- Severe mental illness

DIABETES SELF-MANAGEMENT EDUCATION AND SUPPORT

Diabetes Self-Management Education and Support (DSMES) is an essential component of diabetes treatment. Support from the healthcare professional team augments patients’ necessary knowledge and skills. The four critical times to evaluate the need for DSMES are¹⁴:

at diagnosis
annually and/or when not meeting treatment targets
when compelling factors develop
when transitions in life or care occur.

Collaboration between patients and the healthcare team provides patient-centered DSMES. Thorough DSMES includes counselling on nutrition, physical activity, and psychosocial issues. Digital coaching and self-management interventions can be the means to deliver education and support.¹⁴

Diabetes self-management training (DSMT) is the reimbursable component of DSMES. A health care professional who is a certified Diabetes Care and Education Specialist (CDCES) —generally a dietitian, nurse or pharmacist— administers the DSMT. DSMT covers blood glucose monitoring, physical activity, healthy eating, medication, coping, problem solving.¹⁵

PAUSE AND PONDER: What lifestyle behaviors are fueling the diabetes epidemic?

Nutritional Therapy

Compelling evidence supports nutrition therapy’s efficacy and cost-effectiveness as a component of the medical management of T2DM.¹⁶According to the CDC, a registered dietitian or nutritional professional provides medical nutrition therapy (MNT). MNT focuses solely on diet. Education should encompass in-depth, individualized nutritional assessment and follow-up with repeated reinforcement to aid with behavior change.¹⁷ MNT encourages a diet rich in non-starchy vegetables, whole foods, and limited added sugars and refined grains. Increasing dietary fiber intake is beneficial, as diets high in fiber may lower HbA1c moderately. Minimizing carbohydrate intake improves glycemia. Diets higher in unsaturated fats than carbohydrates improve glycemia, triglycerides, HDL-C, and LDL-C in patients with cardiovascular disease and kidney disease.¹⁶

Caloric goals with an overall energy deficit (calories in are less than calories expected) promoting 5% weight loss have shown clinical benefit in reducing HbA1C. The goal for optimal outcomes in T2DM is to reduce body weight by 15%.¹⁶Dietary intervention can lead to disease remission, defined as sustained HbA1c levels below 6.5% for three months. Those diagnosed with type 2 diabetes for four years or fewer are more likely to achieve remission through diet. However, interventions accompanied by other lifestyle changes can be more effective than diet alone.¹⁸

Physical Activity

The World Health Organization (WHO) recommends adults engage in at least 150 to 300 minutes of moderate-intensity or 75 to 150 minutes of vigorous-intensity physical activity, or a combination of both, per week. Additionally, the WHO recommends reducing sedentary behaviors across all age groups and abilities.¹⁹

According to the CDC, moderate-intensity physical activity includes brisk walking, light yard work, light snow shoveling, biking, or playing with children. Ideally, patients’ heart rates will be 64% to 76% of their maximum. (To calculate actual beats per minute, patients subtract their age from 220, then multiply by 0.64 for the lower limit and by 0.76 for the upper limit.) Vigorous-intensity (high-intensity) exercise is jogging, swimming, rollerblading, cross country skiing, competitive sports, or jumping rope. Ideally, patients’ heart rate will be 77% to 93% of their maximum heart rate. (Calculation of the beats per minute is the same as above using 0.77 and 0.93 as the multipliers.)²⁰

Physical exercise has a positive effect on glycemic control. One study compared baseline glycemic levels with those measured after 30 minutes of moderate exercise before breakfast for three consecutive days. The study found that blood glucose levels were less variable throughout the day after morning exercise.²¹In patients with impaired fasting glucose, progression to diabetes is slower in those who chose leisure time physical activity over sedentary tasks.²² High intensity exercise improves HbA1c more than moderate- or mild-intensity exercise.²³

Researchers conducted an 8-year study of 30 patients with T2DM in which participants engaged in three 90-minute sessions of aerobic exercise per week. The exercise program included a 15-minute warm up and cool down period. During the aerobic period, participants’ exercise intensity gradual increased from 50% to 80% maximum heart rate. Study participants had significantly reduced HbA1c and BMI. Participants also had significantly improved oxygen utilization. The researchers reported a HbA1c significant decrease of 1.39% among the experiment group.²⁴

Physical activity may be the most underutilized tool in T2DM management. Physical activity improves cardiorespiratory fitness, reduces insulin resistance and insulin levels, improves lipid profiles, reduces visceral adipose tissue, and lowers blood pressure, decreasing cardiovascular risk.²⁵ Due to exercise’s overwhelming benefit, developing a structured exercise plan for patients diagnosed with T2DM is a key responsibility for healthcare teams. Ideally, the healthcare care team would include an exercise physiologist.²⁵

PAUSE AND PONDER: What self-care behaviors contribute to effective T2DM self-management?

Psychosocial Support

Up to 19% of patients with diabetes experience mental health symptoms. Depression is common, especially in women. Early detection and treatment of mental health comorbidities can reduce their impact on health outcomes. Mortality risk is higher in patients with mental health comorbidities, especially in those with substance use disorder and schizophrenia. Mental health comorbidities also increase the likelihood of all-cause hospitalization.²⁶

Experts agree that collaborative patient-centered approaches to psychosocial care are best; such approaches include assessing patients for depression, anxiety, disordered eating, and cognitive capacities. Psychosocial screening and follow-up may include attitudes about diabetes, expectations for medical management, and outcomes.⁸

The Association of Diabetes Care and Education Specialists has identified seven self-care behaviors that contribute to effective self-management of diabetes and related conditions through improved behavior²⁷:

being active
healthy coping
healthy eating
monitoring
problem solving
reducing risk
taking medication

Well-educated patients can contribute to their diabetes management with self-care behaviors. Monitoring health metrics like blood glucose, blood pressure, physical activity, diet, weight, medication adherence, mood, and sleep empower diabetes patients and improve outcomes.²⁷Higher medication adherence, as would be expected, is associated with improved glycemic control, fewer emergency department visits, decreased hospitalizations, and lower medical costs.²⁸Patients sharing data with the healthcare team can fuel discussion to find solutions, reduce risk, and improve personalized therapy plans.²⁷

PHARMACOLOGIC THERAPY

First line therapy for T2DM depends on comorbidities, patient-centered treatment factors, and management needs. It frequently includes metformin and comprehensive lifestyle modification. If the patient has atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and/or chronic kidney disease (CKD) then appropriate initial medical therapy may include glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors with or without metformin. Prescribers may continue metformin upon initiation of insulin therapy for ongoing glycemic and metabolic benefits.⁸

Metformin

Apothecaries have used metformin medicinally for centuries. It is a guanidine derivative found in Galega officinalis, a plant called goat’s rue. Metformin was isolated and introduced in Europe in the 1950s and the United States in the 1990s.²⁹ Metformin decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not cause hypoglycemia and patients generally tolerate it well. The most common adverse effect is diarrhea, resulting in 6% of patients discontinuing therapy. Other common adverse effects include nausea/vomiting, flatulence, asthenia, indigestion, and abdominal discomfort. Precautions include the potential for lactic acidosis, especially in patients with the following risk factors³⁰:

Renal impairment
Hepatic impairment
Heart failure
Hypoxic states
Excessive alcohol intake
Radioactive dye studies
Restricted food and fluid intake

Metformin may interfere with vitamin B₁₂ absorption. Approximately 7% of patients become deficient. Supplementation with vitamin B₁₂ is appropriate if deficits develop.³⁰

Metformin can reduce HbA1c by 1.8% and lower the amount of insulin required to achieve glycemic targets by 19%.³¹ Initial dosing is 500 mg twice daily, or 850 mg daily, increasing as tolerated by 500 mg weekly to a maintenance dose of 1000 mg twice daily in patients with normal renal function. The maximum recommended dose is 2,550 mg per day. Monitoring fasting plasma glucose during initiation and dose titration aids in determining therapeutic response. Maintenance measurement of HbA1c levels should occur every three months.³⁰Renal function is an important factor in metformin use. The recommended eGFR threshold for initiation of metformin is 45 mL/min. If, during therapy, the eGFR falls below 45 mL/min, the team need to assess the benefit of continued therapy. Use is contraindicated in patients with an eGFR below 30 mL/min.³⁰

INSULIN THERAPY

ADA Standards of Care recommend early introduction of insulin if clinicians see evidence of ongoing weight loss, symptoms of hyperglycemia, HbA1c levels exceeding 10%, or blood glucose levels of 300 mg/dL or higher. The potential for over-basalization (titration of basal insulin beyond an appropriate dose in an attempt to achieve glycemic targets) exists with insulin therapy. Signs of over-basalization may include a basal dose exceeding 0.5 units/kg/day, high bedtime-morning or post-prandial glucose differential, hypoglycemia, and high glycemic variability.⁸

When caring for hospitalized patients with diabetes, basal insulin or a basal plus bolus correction insulin is the preferred treatment for noncritically ill patients with poor oral intake. The standards prefer an insulin regimen with basal, prandial, and correctional components in patients with good nutritional intake. In many hospital settings, the basal and prandial doses are weight-based, and a correctional scale is added to scheduled mealtime doses to correct for pre-meal hyperglycemia.

It’s critical to initiate insulin therapy for persistent hyperglycemia at a threshold of 180 mg/dL or more, confirmed on two occasions. After initiating insulin, the current Standards of Care recommend a target glucose range of 140 to 180 mg/dL for most patients. More stringent goals, such as 110 to 140 mg/dL, may be appropriate for select patients if they do not exhibit significant hypoglycemia. The ADA defines hyperglycemia as blood glucose levels over 140 mg/dL in the hospital, and hypoglycemia as blood glucose below 70 mg/dL. Monitoring glucose every four to six hours or every two hours for an insulin infusion is best. Each hospital or hospital system should implement hypoglycemic management protocols.⁸

TREATMENT RECOMMENDATIONS IN COMMON COMORBIDITIES

Obesity

High BMI is the primary risk factor for T2DM.⁵Diabetes was the second leading cause of BMI-related deaths in 2015 globally.³² The DIRECT trial showed a T2DM remission rate of 36% after 24 months in patients receiving structured support for initial weight loss and weight loss maintenance.³³The 2022 ADA Standards of Medical Care in Diabetes categorize obesity treatment options based on BMI⁸:

Nonpharmacologic strategies may be sufficient for those with BMI 25 to 26.9
Providers should consider adding pharmacotherapy for those with a BMI of 27 to 29.9
For those with a BMI exceeding 30 (or for Asian Americans with BMI 27.5 and over), patients and their treatment teams might consider metabolic surgery

The Standards of Care in Diabetes stress a minimum of 5% weight loss for most people with T2DM. It is important to include counseling with two to three monthly sessions focusing on dietary changes, physical activity, and behavioral strategies to achieve a 500 to 750 kcal/day energy deficit. Person-centered, nonjudgmental language, specifically “person with obesity” rather than “obese person,” fosters collaboration between patients and providers. Consideration of the medication’s effect on weight gain is important.⁸ Metformin, SGLT-2 inhibitors, GLP-1 receptor agonists, alpha-glucosidase inhibitors, and amylin mimetics promote weight loss.³⁴

As of November 2023, three FDA-approved obesity medications also have FDA approval for treating T2DM. These are the GLP-1 agonists liraglutide, semaglutide, and tirzepatide.^35,36Dosages are as follows^37-39:

Liraglutide (Saxenda) has an initial dose of 0.6 mg/day with a maintenance dose of 3 mg/day
Semaglutide (Wegovy) has an initial dose of 0.25 mg/week with a maintenance dose of 2.4 mg/week
Tirzepatide (Zepbound) has an initial dose of 2.5 mg/week with a maintenance dose of 5 to 15 mg/week

The FDA has approved these medications for weight loss in patients with a BMI of 30 or above or BMI of 27 or above with a comorbidity including hypertension, T2DM, or dyslipidemia.^37-39 These drugs lower glucose by stimulating insulin secretion from pancreatic islets in response to oral glucose load, like the natural hormone incretin. They delay gastric emptying, suppress appetite, increase satiety, decrease inappropriate glucagon secretion, and promote beta cell proliferation.^40,41

Clinical data for the GLP-1 medications in weight loss is impressive. The SCALE trial has shown that the absolute weight loss with liraglutide 3 mg daily in patients with T2DM is 5.6 kg (12.3 lbs) over 56 weeks.⁴²The absolute weight loss associated with semaglutide 2.4 mg weekly in obese patients or overweight patients with at least one risk factor is 12.7 kg (28 lbs) over 68 weeks.⁴³Diabetic patients treated with tirzepatide 5, 10 or 15 mg weekly for 72 weeks lost an average of 12% body weight compared to placebo.³⁹ These medications contain warnings and precautions for thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, hypoglycemia with some T2DM medications, kidney injury, hypersensitivity reactions, and suicidal ideation.^37-39 The labeling for semaglutide and tirzepatide carries a precaution for diabetic retinopathy.^38,39 A precaution for heart rate increase is included in the labeling for liraglutide and semaglutide.^37,38 Most patients find these drugs have overwhelming benefits with primarily gastrointestinal adverse effects.^36-38

Providers may consider metabolic surgery for T2DM treatment in adults with a BMI of 30 and over (or for Asian Americans with a BMI of 27.5 and greater). Metabolic surgery refers to surgical organ modification; bariatric surgery, for example, is metabolic surgery for treatment of obesity (commonly known as a gastric bypass). A high-volume surgical center with experienced multidisciplinary teams knowledgeable about obesity management, diabetes, and gastrointestinal surgery is the best choice. Access to long-term medical, nutritional, and behavioral support after the procedure optimizes recovery. Patients may benefit from continuous glucose monitoring as an important adjunct, especially for those with episodes of hypoglycemia. After surgery, the clinical team should provide patient support, including mental health services.⁴⁴

Bariatric surgery is an effective treatment option in T2DM patients with obesity. In a recent study, after a median follow-up of 19 months post-surgery, 68 of 105 obese patients achieved diabetes remission. Study participants had a median BMI of 42.4 and a diagnosis of T2DM before the procedure. Patients taking multiple glucose-lowering medications or dependent on insulin or SGLT2 inhibitors were less likely to undergo complete remission. A longer duration of T2DM pre-operatively was a negative predictor of remission.⁴⁵

PAUSE AND PONDER: Which classes of diabetes medications are best for patients with ASCVD?

Cardiovascular Disease

All diabetic patients require yearly assessment of HF and ASCVD (coronary artery disease, cerebrovascular disease, or peripheral arterial disease). Hypertension, dyslipidemia, and diabetes are risk factors for ASCVD. Controlling cardiovascular risk factors can prevent or slow ASCVD in people with diabetes.⁴⁶

Prescribers should consider the presence of coronary artery disease in patients exhibiting atypical cardiac symptoms, signs of vascular disease, or electrocardiogram abnormalities. Atypical cardiac symptoms include unexplained dyspnea or chest discomfort. Carotid artery stenosis, transient ischemic attack, stroke, and peripheral arterial disease are indicators of ASCVD.⁴⁶

In T2DM patients with established ASCVD or kidney disease, current ADA Standards of Medical Care suggest an SGLT-2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular disease benefit (see Table 1 and Table 2). A quick review of FDA indications and landmark trials ensures the correct medication and dose have been chosen as newer agents continue to emerge with indications that may encompass weight loss and treatment of T2DM. To reduce the risk of adverse cardiovascular and kidney events, patients with T2DM and established ASCVD may benefit from combined therapy with an SGLT-2 inhibitor and a GLP-1 receptor agonist with demonstrated cardiovascular benefit.⁴⁶

Table 1. Landmark Trials for SGLT-2 Inhibitors Evaluating T2DM with Cardiovascular Disease^47-50

Trial	Drug	Outcome
EMPA-REG OUTCOME	Empagliflozin 10-25 mg daily	Reduction in major adverse cardiovascular events; Reduction in hospitalization for heart failure
CANVAS	Canagliflozin 300 mg daily goal	Reduction in major adverse cardiovascular events; Reduced hospitalization for heart failure and cardiovascular death
DECLARE-TIMI 58	Dapagliflozin 10 mg daily	Reduction in heart failure-related death and hospitalization; Reduction in renal events

The SGLT-2 inhibitors’ primary mechanism of action is reduction of renal tubular glucose reabsorption at the proximal tubule resulting in glucosuria.⁵¹ The SGLT-2 inhibitors’ glucose-lowering efficacy decreases with increasing renal impairment.⁵² Most patients tolerate these medications well, with mild adverse effects. The proposed cardiovascular benefits include improved, blood pressure reduction, inflammation reduction, diuresis, inhibition of nervous system, and prevention of cardiac remodeling (physical changes to heart).⁴⁷ Their adverse effects include genitourinary infections, intravascular volume depletion, increased risk of diabetic ketoacidosis, and potentially an increased risk of lower limb amputations.⁵² Prescribers need to hold SGLT-2 inhibitors during acute illness (hospitalization), when fluid intake is inadequate, or if acute kidney injury occurs.⁴⁷

Pancreatic hormones and incretin hormones regulate glycemic homeostasis. GLP-1 is an incretin hormone that increases pancreatic insulin release and decreases glucagon release.⁴¹ The GLP-1 receptors are located in the renal proximal convoluted tubular cells and preglomerular vascular smooth muscle cells in the kidneys.⁵³ The GLP-1 receptor agonists lower HbA1c, weight, and blood pressure.⁵⁴

GLP-1 receptor agonists promote natriuresis (increased sodium in the urine), lowering blood pressure.⁵⁵ GLP-1 receptor agonists also reduce reactive oxygen production, thereby reducing platelet activation, macrophages, and monocytes in the vascular wall. Stabilization of the endothelial cells occurs with less plaque hemorrhage and rupture.⁵⁶ Overall, GLP-1 enhancement results in a slower progression of atherosclerosis.⁵⁷

Table 2. Landmark Trials for GLP-1 Agonists: Evaluating T2DM with Cardiovascular Disease^57-60

Trial	Drug	Outcome
REWIND	Dulaglutide 1.5 mg once a week	Reductions in major adverse cardiovascular events
SUSTAIN-6	Semaglutide 0.5 or 1 mg once a week	Relative risk reduction in major adverse cardiovascular events
LEADER	Liraglutide 1.8 mg (or max dose tolerated) daily	Relative risk reduction in major adverse cardiac events and cardiovascular death

In T2DM patients with a history of ASCVD, aspirin 75 mg to 162 mg daily is a secondary prevention strategy. In patients with documented aspirin allergies, clopidogrel 75 mg daily is an alternative. Patients with stable coronary and or peripheral artery disease and a low bleeding risk should take dual antiplatelet therapy for at least one year following acute coronary syndrome. Aspirin and low dose rivaroxaban can prevent major adverse limb and cardiovascular events.⁶¹

Hypertension

Hypertension exacerbates cardiovascular disease, which is the major cause of morbidity and mortality in diabetes.⁶² In 2023, the ADA updated the hypertension criteria. According to the 2023 Standards of Care in Diabetes recommendations, patients are hypertensive if they exhibit a sustained blood pressure of 130/80 mm Hg or more, or a single level of 180/110 or more. The target goal is 130/80 mm Hg or less. Blood pressure targets below 120/80 mmHg are associated with hypotensive adverse events (such as falls). Patients with diabetes who are hypertensive should monitor their blood pressure at home. Patients with blood pressures exceeding 120/80 should implement lifestyle interventions including diet changes and weight loss, reduced sodium and increased potassium intake, moderation of alcohol, and increased physical activity.⁶¹ Treatment of hypertension reduces cardiovascular events and microvascular complications.^63,64

In patients with persistently elevated blood pressure, pharmacologic therapy in addition to lifestyle modifications improves outcomes. First-line pharmacologic therapy includes use of an angiotensin-converting enzyme inhibitor (ACEi), or an angiotensin receptor blocker (ARB). Clinical trials assessing these drugs demonstrate a reduction of cardiovascular events in T2DM patients with coronary artery disease. Prescribers should maximize doses for patients with a urine-to-creatinine ratio greater than 30 mg/g creatinine, as this is a sign of kidney damage. If the patient does not tolerate one drug class, the prescriber may switch to the other; however, the prescriber should not use them together. Annual monitoring of glomerular filtration rate (GFR) and serum potassium are needed.⁶¹

Prescribers should start their patients on two medications if they have a confirmed office blood pressure of 160/100 mm Hg or more.⁶¹ Common therapies include thiazide-like diuretics and dihydropyridine calcium channel blocker.⁶⁵ Patients on triple antihypertensive therapy including a diuretic with unmet blood pressure goals may require a mineralocorticoid receptor antagonist, such as spironolactone.⁶⁶ Adding a mineralocorticoid receptor antagonist may increase the risk of hyperkalemia. Regular monitoring of serum creatinine and potassium is prudent.⁴⁶

In the absence of albuminuria, ACEi and ARBs may not provide superior cardio-protection over thiazide-like diuretics or dihydropyridine calcium channel blockers.⁶⁷ Patients who have had a prior myocardial infarction, active angina, or HF with reduced ejection fraction (HFrEF) should be treated with a beta blocker. However, beta blockers do not reduce mortality when used as antihypertensives in the absence of these conditions.^54,68

Hyperlipidemia

Reduction of lipids and cholesterol is important because hyperlipidemia is a risk factor and common comorbidity for T2DM. Lifestyle modification focusing on weight loss is the first step of lipid management. Trained nutritionists can educate patients to eat a diet low in saturated fat and trans-fat. The goal is a diet that increases dietary n-3 fatty acids, viscous fiber, and plant stanols/sterols. Physical activity also helps improve lipid profiles. The importance of lifestyle therapy and glycemic optimization for triglycerides of 150 mg/dL or greater, and/or HDL equal to or less than 40 mg/dL for men and 50 mg/dL for women, cannot be understated. Lipid profiles at the time of diabetes diagnosis, at initiation of statin therapy or dose change, and annually thereafter are useful to monitor disease progression.⁶¹

Statin therapy has documented beneficial outcomes in patients with ASCVD.^69,70 The intensity of dosing is outlined below (see Table 3)⁶¹:

Patients with diabetes aged 40 to 75 without ASCVD should begin moderate-intensity statin therapy in addition to lifestyle therapy.
Patients with diabetes aged 40 to 75 years and multiple ASCVD risk factors should take high intensity statin therapy to reduce LDL cholesterol by at least 50% of baseline for an LDL target of less than 70 mg/dL.
Patients with diabetes and ASCVD should take high-intensity statin therapy. Prescribers may add ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, such as alirocumab or evolocumab, to achieve a goal of LDL below 55 mg/dL and an LDL reduction of 50% or more.

Table 3. Once daily: High-intensity and Moderate-intensity Statin Therapy⁶¹

Moderate-intensity statin therapy	High-intensity statin therapy
Atorvastatin 10–20 mg	Atorvastatin 40–80 mg
Rosuvastatin 5–10 mg	Rosuvastatin 20–40 mg
Simvastatin 20–40 mg
Pravastatin 40–80 mg
Lovastatin 40 mg
Fluvastatin (extended release) 80 mg
Pitavastatin 1–4 mg

Heart Failure

HF is a major cause of morbidity and mortality from cardiovascular disease. Recent studies indicate that people with diabetes have twice the risk of hospitalization due to HF compared to those without, after adjusting for age and sex.^71,72 Patients with established T2DM have a 33% greater risk of hospitalization for HF.⁷¹

HF is staged as A to D. Stage A HF indicates risk for developing HF. All patients with established diabetes are in the stage A category and at heightened risk for progression to later stages of HF. Stage B HF is asymptomatic with structural heart disease, abnormal cardiac function, or elevated cardiac biomarkers. Prescribers should monitor biomarkers, natriuretic peptide (BNP), or high sensitivity cardiac troponin yearly to detect subclinical HF in individuals with diabetes. Monitoring helps identify those in stage A or B HF who are at the highest risk of progressing to symptomatic HF. Useful cutoff values for these indicators are a BNP of 50 pg/mL and a NT-proBNP of 125 pg/mL.⁷³

Individuals considered to be at stages C and D have had or are experiencing symptomatic HF. Common symptoms are exertional dyspnea (shortness of breath), fatigue and edema that reflect fluid retention, congestion, and low cardiac output. Laboratory evaluations for patients with HF include natriuretic peptide, complete blood count, urinalysis, serum electrolytes, blood urea nitrogen, serum creatinine, glucose, fasting lipid profile, liver function, and thyroid stimulating hormone. Additionally, prescribers should order a chest x-ray and 12 lead electrocardiogram.⁷³

In stage A or B HF patients with diabetes and hypertension, medical therapy includes an ACEi or ARB. Clinical trials have found that treatment with a thiazide-type diuretic or an ACEi is more effective than treatment with a calcium channel blocker in preventing progression to symptomatic HF. Patients with diabetes and diabetic kidney disease (DKD) without symptomatic HF may benefit from finerenone, a nonsteroidal mineralocorticoid receptor antagonist.⁷³

Standards of Care recommendations for those with HFrEF and diabetes include an angiotensin receptor/neprilysin inhibitor (ARNI) or ACEi or ARB, beta blockers, mineralocorticoid receptor antagonist, and SGLT-2 inhibitor. In individuals with diabetes and HFrEF, including an ARNI (sacubitril/valsartan) instead of ACEi or ARBs is prudent. It is reasonable to consider treatment with spironolactone among individuals with heart failure with preserved ejection fraction (HFpEF) as well. Clinical trials have shown that treatment with an SGLT-2 inhibitor reduces HF hospitalizations.⁷²Individuals with high cardiovascular risk, including those with stage B HF and those with symptomatic HF, should take an SGLT-2 inhibitor. Prescribers may consider statins based on age and background risk factors. Treatment for patients requiring additional glycemic control may include a GLP-1 agonist, metformin, or both, or insulin. Current Standards of Care do not recommend the use of dipeptidyl peptidase-4 (DPP) inhibitors or thiazolidinediones in T2DM patients with stage B, C or D HF.⁷³

In addition to drug therapy, participation in cardiac rehabilitation is associated with improved patient outcomes. Cardiac rehabilitation involves exercise training, education, and emotional support. Key counseling points for patient with diabetes and HF are to minimize alcohol intake and avoid smoking. Weight loss improves cardiometabolic risk factors. Metabolic surgery can improve risk factors for HF in obese patients.⁷³

Chronic Kidney Disease

Diabetes is the leading cause of kidney disease in the developed world.⁷⁴ The presence of CKD markedly increases cardiovascular risk and health care costs.⁷⁵ Practitioners diagnose CKD primarily by sustained elevation of urinary albumin excretion and low estimated glomerular filtration rate (eGFR).⁷⁶

Recommendations include yearly assessment of eGFR and urinary albumin in all T2DM patients. In patients with established DKD, monitoring up to four times yearly may be necessary.⁷⁶ Consistent eGFR values less than 60 mL/min, in conjunction with a urinary albumin value over 30 mg/g creatinine defines an abnormal eGFR.⁷⁷ The definition of stage 1 and 2 CKD is high albuminuria with eGFR 60 mL/min or above. CKD stages 3-5 have progressively lower eGFR ranges.⁷⁸ At any eGFR, the degree of albuminuria is associated with risk of cardiovascular disease, CVD progression, and mortality.⁷⁵

Current ADA Standards of Care emphasize optimization of blood pressure and blood glucose to reduce the risk of and slow CKD progression.⁷⁶ ACEi or ARBs are the preferred first-line agents for blood pressure treatment in T2DM patients with hypertension and decreased eGFR.^79,80 The healthcare team needs to continue renin-angiotensin system blockade for increases in serum creatinine of 30% or less in the absence of volume depletion. In addition, it needs to monitor serum potassium levels when patients take ACE inhibitors, ARBs, or diuretics.⁷⁶

Recent trials show SGLT-2 inhibitor therapy reduces CKD progression and cardiovascular events in patients with CKD, T2DM, and an eGFR of 20 mL/min/1.73m² or greater.⁷⁶ SGLT-2 inhibitors reduce renal tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, albuminuria, and slow GFR loss through mechanisms that are independent of glycemia.⁸¹ To minimize cardiovascular events, addition of a glucagon-like peptide 1 agonist may help, or a nonsteroidal mineralocorticoid receptor antagonist (nsMRA) if eGFR is 20 mL/min/1.73m². For patients with urinary albumin of 300 mg/g or greater, reduction of at least 30% slows CKD progression.⁷⁶ Suggested daily protein intake in CKD stage 3 (non-dialysis) patients is 0.8 g/kg body weight per day. Higher levels of protein have been associated with increased albuminuria and more rapid kidney function loss.⁸² If the eGFR falls below 30, a nephrologist referral is needed.⁷⁶

Tables 4 and 5 list recent trials that support current ADA Standards of Care regarding treatment of diabetes in the presence of CKD.⁷⁶ In the CREDENCE trial, canagliflozin therapy reduced the development of ESRD by 32% in patients with CKD.⁸³ The DAPA-CKD trial studied dapagliflozin in CKD. Two thirds of the patients had a diabetes comorbidity. There was significant benefit for a decline in eGFR, ESRD or death from cardiovascular or renal causes.⁸⁴ The FIDELIO-DKD trial studied the nonsteroidal mineralocorticoid receptor antagonist, finerenone. The trial identified a significant reduction in DKD progression and cardiovascular events in people with advanced kidney disease. Participants took finerenone 10 to 20 mg daily. Evaluation after a mean of 3.4 years demonstrated a 23% reduction in the composite kidney outcome consisting of sustained decrease in eGFR of at least 57%.⁸⁵

Table 4. Landmark Trials for SGLT-2 inhibitors in renal disease^47,83,84,86

Trial	Drug	Outcome
CREDENCE	Canagliflozin 100 mg daily	Cardiovascular and renal protection
DAPA-CKD	Dapagliflozin 10 mg daily	Reduction of eGFR decline; Reduction of ESRD; Reduction of renal mortality
EMPA-KIDNEY	Empagliflozin 10 mg daily	Reduced progression of kidney disease; Reduced cardiovascular death

Table 5. Landmark Trials for GLP-1 Receptor Agonists in T2DM and Renal Disease^57,58,87,88

Trial	Drug	Outcome
AWARD-7	Dulaglutide 0.75 -1.5 mg once a week	Slower decline in eGFR. No change in urine albumin-creatine ratio
LEADER	Liraglutide 1.8 mg (or max dose tolerated) daily	Reduced the development and progression of diabetic kidney disease
REWIND (analysis)	Dulaglutide 1.5 mg once a week	Relative risk reduction in composite renal outcome

CONCLUSION

T2DM is indeed a growing epidemic fueled by an unhealthy diet and a sedentary lifestyle.¹ A prescription is only a partial answer to a multifactorial problem. This is why the ADA Standards of Care for diabetes incorporate a multidisciplinary approach focusing on individuals, their current disease states, and preventive measures for disease progression. Recommendations emphasize the importance of self-management, education, and support. Nutritional therapy, physical activity, and psychological support are key elements. Effective weight management is a powerful tool for managing or even reversing T2DM. Current therapy recommendations also incorporate the use of cardiovascular protective medications with demonstrated efficacy for ASCVD.⁸

Due to the high prevalence of comorbid conditions associated with T2DM, it is fortunate that the SGLT-2 inhibitors and GLP-1 receptor agonists are a resource for patients with T2DM comorbidities. These agents improve cardiovascular function and are compatible with guideline-based preventive recommendations for blood pressure, lipids, glycemia, and antiplatelet therapy.^51,89 Diabetes treatment has entered a new era of understanding. The overwhelming data favors addressing the whole patient including lifestyle, education, weight loss options, and cardiovascular related comorbidities. The new ADA Standards of Medical Care provide clinicians with the knowledge and tools to treat the growing diabetic epidemic.

Management of Adults with Type 2 Diabetes: A Patient-Focused Approach

Post-test Questions for Pharmacists

Learning Objectives (pharmacists)
● Describe type 2 diabetes diagnostic criteria and glycemic targets
● Identify the components of diabetes self-management education and support
● Recognize the importance of an individualized treatment program
● List treatment recommendations for diabetes type 2 in the setting of common comorbidities

1. Which of the following is TRUE about the incidence of the global diabetes epidemic?
a. The incidence has quadrupled in the past three decades with a current estimate of about 1 in 11 adults affected worldwide
b. The incidence has doubled in the past four decades with a current estimate of about 1 in 15 adults affected worldwide
c. The incidence has tripled in the past decade with a current estimate of about 1 in 8 adults affected worldwide

2. Which group of people is LEAST LIKELY to be diagnosed with diabetes in the US?
a. Those below the federal poverty level
b. Native Americans and Alaska natives
c. Non-Hispanic whites with college degrees

3. According to ADA Standards of Medical Care in Diabetes, pharmacologic therapy options for patients with HFrEF and diabetes may include all of the following drug classes EXCEPT?
a. ARNI
b. SGLT2 inhibitor
c. DPP-4 inhibitors

4. What is the focus of DSMES?
a. Nutrition, relaxation, and psychosocial issues
b. Nutrition, physical activity, and psychosocial issues
c. Physical therapy, psychotherapy, and natural dietary supplements

5. Which of the following statements about diet is TRUE?
a. Diet as a primary intervention for T2DM can achieve remission, defined as sustained HbA1c levels under 6.5% for 3 months
b. Diets low in fats and higher in carbohydrates are recommended for those with T2DM due to the risk of cardiovascular disease
c. Sustaining calorie intake and monitoring blood glucose levels is often the best course of action for those recently diagnosed with T2DM

6. Which statement is true regarding physical activity and diabetes?
a. The World Health Organization guidelines state that those with diabetes should exercise less than 75 minutes per week.
b. Aerobic exercise before breakfast increases blood glucose levels.
c. In patients with impaired fasting glucose progression to diabetes is slower in those who chose leisure time physical activity over sedentary tasks.

7. Which of the following self-care behaviors is an effective self-management tool for diabetes?

a. Healthy coping, healthy eating, being active, taking medication, monitoring, reducing risk, and problem solving
b. Healthy coping, healthy eating, resting, taking medication, monitoring, reducing risk, and spending time with family
c. Healthy coping, healthy eating, being active, taking medication, monitoring, reducing risk, and allowing your doctor to decide the best way for you to manage your diabetes independently

8. Which statement best defines the current ADA Standards of Medical Care in Diabetes recommendations?
a. All diabetic patients should follow a step-up drug therapy algorithm developed by the American Diabetes Association to meet glycemic targets.
b. Regardless of comorbidities, initial treatment of T2DM should include hypoglycemic agents such as sulfonylureas supplemented by insulin, if needed, to achieve a HgA1c of 7% or lower
c. First line therapy for T2DM depends on comorbidities, patient centered treatment factors and management needs.

9. Under what circumstances should initial treatment include insulin?
a. If there is ongoing weight loss, symptomatic hyperglycemia, A1C levels over 10%
b. If there is fluid overload, symptomatic hypoglycemia or A1C levels over 8%
c. If the patient has chronic kidney disease, heart failure or chronic obesity

10. For a patient with diabetes whose eGFR > 20, which comorbidity would benefit most from a medication regimen containing an ACEi, SGLT2 inhibitor, and a GLP-1 agonist or a nsMRA?

a. Chronic kidney disease
b. Hypertension
c. Hyperlipidemia

Management of Adults with Type 2 Diabetes: A Patient-Focused Approach

Post-test Questions for Pharmacy Technicians

Learning Objectives (technicians)
● Describe type 2 diabetes diagnostic criteria and glycemic targets
● Identify the components of diabetes self-management education and support
● Recognize the importance of an individualized treatment program
● List common comorbidities in type 2 diabetes

3. Which laboratory data would lead to a positive diagnosis of diabetes?
a. A hemoglobin A1c level of 6.0%
b. A 2-hour plasma glucose level of 200 mg/dL or higher during a 75 gram oral glucose tolerance test
c. A fasting plasma glucose level of 120 or higher

6. Which statement is true regarding physical activity and diabetes?
a. The World Health Organization guidelines state that those with diabetes should exercise less than 75 minutes per week.
b. Aerobic exercise before breakfast has increases blood glucose levels.
c. In patients with impaired fasting glucose progression to diabetes is slower in those who chose leisure time physical activity over sedentary tasks.

7. Which of the following self-care behaviors is an effective self-management tool for diabetes?

8. According to the new 2023 ADA Standards of Medical Care in Diabetes, patients are hypertensive if they exhibit a sustained blood pressure above which level?
a. 140/90 or more
b. 130/80 or more
c. 120/80 or more

9. Which of the following lists accurately describes the most common comorbidities in type 2 diabetes?

a. Cardiometabolic, vascular, and mental health conditions
b. Cardiometabolic, vascular, and dermatologic conditions
c. Cardiac, gastrointestinal, and mental health conditions

10. How much more is risk of heart failure hospitalization in people who have type 2 diabetes?

a. 33%
b. 50%
c. 77%

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70. Baigent C, Keech A, Kearney PM, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet. 2005;366(9493):1267–1278. doi: 10.1016/S0140-6736(05)67394-1
71. Cavender MA, Steg PG, Smith SC, Eagle K, Ohman EM, Goto S, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death. Circulation. 2015;132(10):923–31. doi: 10.1161/CIRCULATIONAHA.114.014796
72. McAllister DA, Read SH, Kerssens J, et al. Incidence of Hospitalization for Heart Failure and Case-Fatality Among 3.25 Million People With and Without Diabetes Mellitus. Circulation. 2018;138(24):2774–2786. https://doi.org/10.1161/CIRCULATIONAHA.118.034986
73. Pop-Busui R, Januzzi JL, Bruemmer D, et al. Heart Failure: An Underappreciated Complication of Diabetes. A Con-sensus Report of the American Diabetes Association. Diabetes Care. 2022;45(7):1670–1690. https://doi.org/10.2337/dci22-0014
74. De Boer IH, MD, MS; Rue TC, MS; Hall YN, MD; et al. Temporal Trends in the Prevalence of Diabetic Kidney Dis-ease in the United States. JAMA. 2011;305(24):2532-2539. doi:10.1001/jama.2011.861
75. Fox CS, Matsushita K, Woodward M, et al.; Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380(9854):1662–1673. doi: 10.1016/S0140-6736(12)61350-6
76. ElSayed NH; Aleppo G; Aroda VR; on behalf of the American Diabetes Association. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S191–S202. https://doi.org/10.2337/dc23-S011
77. National Kidney Foundation. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013; 3(1):1–148. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf
78. Levey AS, Coresh J, Balk E, et al.; National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003;139(2):137–147. doi: 10.7326/0003-4819-139-2-200307150-00013
79. HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE sub study. Lancet 2000;355(9200):253-9
80. Shaikh A, A Practical Approach to Hypertension Management in Diabetes. Diabetes Ther. 2017;8(5):981–989. doi: 10.1007/s13300-017-0310-3
81. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018; 72(15):1845–1855. doi: 10.1016/j.jacc.2018.06.040
82. Klahr S, Levey AS, Beck GJ, et al.; Modification of Diet in Renal Disease Study Group. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med. 1994; 330(13):877–884. doi: 10.1056/NEJM199403313301301
83. Perkovic V, Jardine MJ, Neal B, et al., for the CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019; 380:2295-2306. doi: 10.1056/NEJMoa1811744
84. Herrspink, HJ, Stefansson, BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi: 10.1056/NEJMoa2024816
85. Bakris GL, Agarwal R, Anker SD, et al, for the FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020; 383:2219-2229. doi: 10.1056/NEJMoa2025845
86. EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388:117-127. doi: 10.1056/NEJMoa2204233
87. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018;6(8):605-617. doi: 10.1016/S2213-8587(18)30104-9
88. Mann JF, Orsted DD, Brown-Frandsen K, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377:839-848. doi: 10.1056/NEJMoa1616011
89. Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovas-cular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Over-sight Committee. J Am Coll Cardiol. 2020;76:1117-1145. doi: 10.1016/j.jacc.2020.05.037

Law: People are not Cows and Off-label Prescribing is Utterly Different – RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-24-018-H03-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

1. Off label drug uses generally do not become on-label uses. What is a primary reason for this?
A. There is a financial disincentive to manufacturers.
B. The FDA has no easy mechanism to accomplish this.
C. Manufacturers want to emphasize their drug’s primary.

2. You have a sick cow. Which of the following is correct about the type of drug that can be used for treatment?
A. Any drug approved by the FDA for human use.
B. A drug approved for use in chickens if there is no comparable drug approved for cows.
C. A drug that can be compounded by a pharmacist and added to the cow's feed.

3. What category of drugs has the highest rate of off-label use? (Prior to the pandemic.)
A. Anti-seizure drugs
B. Anti-depressants
C. Antibiotics
4. Why does the FDA take a hands-off approach to off-label use?
A. The FDA is not permitted to prevent manufacturers from touting an unapproved use once a drug has been approved.
B. The FDA does not regulate the practice of medicine.
C. The FDA can only act after it receives information of unintended consequences from off-label use.

5. When may a pharmacist recommend an OTC human drug for an animal?
A. Under any circumstances so long as it is not a food animal.
B. When there is no comparable veterinary product available.
C. A pharmacist may not recommend a human OTC drug for use in an animal.

6. Which of the following is a notable risk associated with illicit use of xylazine?
A. Naloxone-resistant overdose
B. Whole body rash and desquamation
C. Respiratory depression

7. The FDA was sued for publishing a warning about the off-label use of ivermectin for COVID. What was the basis of the lawsuit?
A. The FDA cannot prevent physicians from prescribing a drug off-label and need not issue warnings.
B. The FDA's warning on ivermectin was erroneous and used misplaced humor to try to sway opinions.
C. In publishing warning overstepped the FDA’s authority and interfered with the doctor-patient relationship.

Compounding: Go Hog Wild: Creative (and Informed) Veterinary Compounding – RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-24-019-H07-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

1. Farmer Brown's large Maine Coon cat needs fluoxetine. Considering size, anatomy, and skin absorption, which animal would require a similar dose of fluoxetine transdermal gel?
A . A small terrier dog
B. A medium sized sphinx (hairless) cat
C. A large barn owl

2. Meow-Meow is a domestic American cat. She weighs 6.3 pounds, although she needs to gain at least 3 pounds. She needs medication for her heart condition, and the veterinarian wants to prescribe lisinopril 0.25 mg/kg once daily. YIKES! You calculate that Meow-Meow weighs 2.9 kg and needs a dose of 0.725 mg of lisinopril. Can you compound this dose?
A. No, the veterinarian needs to find a different medication
B. Yes, but it would be easier to give 1.5 mg every other day
C. Yes, because a commercial product is unavailable in this strength

3. Your 30-pound hound, Bosco, is begging to eat the food you left on your plate after dinner. In keeping with your house rule never to feed the dog from the table, you take your plate to the sink and get Bosco’s bowl. Which of the following things should you throw in the trash rather than feed to Bosco?
A. The piece of grilled, boned ribeye steak
B. The grapes and raisins on the salad
C. The plain baked potato with yogurt

4. Your client, Venice Marriot, needs to have a medication compounded for her teacup chihuahua Tokyo. She indicates that she and Tokyo prefer medications that are pink. After discussing the pros and cons of compounding with color, which food coloring should you use to make a pink oral solution?
A. Natural beet extract
B. FD&C Red No. 3
C. Neither

5. Which of these basic oral paste formulas would be best to use for Farmer Brown’s cat?
Ingredient Formula 1 Formula 2 Formula 3
Polyethylene glycol 300 65 grams 25 grams
Polyethylene glycol 3350 35 grams 25 grams 25 grams
Propylene glycol 50 grams 25 grams
Molasses (for horses) 50 grams

A. Formula 1
B. Formula 2
C. Formula 3

6. Which flavoring would be best suited for a picky Emperor penguin at Mystic Aquarium?
A. Orange or mango flavoring
B. Sardine or tuna flavors
C. Beef or liver flavoring

7. What Is the BEST way to improve pharmacy personnel’s knowledge of veterinary medications?
A. Pharmacies can be sure to have a veterinary drug handbook at the pharmacy and that the computer system flags veterinary precautions.
B. Pharmacists can complete a continuing education activity on veterinary pharmacy and require all other staff members to take it also.
C. Pharmacy owners and systems can take out extra liability insurance and pray that nothing happens to any animal that receives a prescription from their pharmacies.

Animal Models of Disease: Barking up the Right Tree – RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-24-022-H01-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

The Human-Animal Bond: How Close Is Too Close? – RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-24-021-H01-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

The Human-Animal Bond: How Close is Too Close?

Recognize and describe different zoonotic diseases: Rabies, Lyme Disease, Ringworm (Dermatophytosis), Leptospirosis, Giardia, and Toxoplasmosis
Describe method of transmission of each disease
List the treatment of each disease (if possible)
Indicate the species of animal that can harbor the disease
Describe how to prevent the disease

1. At what age is the earliest a dog or cat can receive the rabies vaccination?
A. 8 weeks
B. 6 months
C. 12 weeks

2. What is the symptom of Lyme Disease in dogs that owners tend to notice first?
A. Shifting lameness
B. Vomiting
C. Increased thirst and urination (PUPD)

3. What is the best way to prevent most zoonotic infections?
A. Avoid wildlife
B. Use essential oils
C. Wash your hands

4. What antibiotic do veterinarians use most often to treat Spirochete bacterial infections?
A. Doxycycline
B. Clindamycin
C. Amoxicillin-clavulanic Acid

5. How are most zoonotic intestinal parasites are spread?
A. Aerosolized
B. Infection through break in the skin
C. Fecal-oral

6. What zoonotic disease causes an itchy, circular red lesion on the skin?
A. Lyme disease
B. Ringworm
C. Leptospirosis

7. What species most commonly carries toxoplasma?
A . Cats
B. Dogs
C. Ferrets

Patient Safety: Teaching Old Dogs New Tricks: Dispensing for Companion Animals in Community Pharmacy – RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-24-020-H05-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Acne Vulgaris Pathogenesis and Treatment

Acne vulgaris is common. It presents with inflammatory and non-inflammatory lesions primarily on the face and trunk. While acne vulgaris is not associated with mortality, it causes a great deal of physical and psychologic sequelae such as permanent scarring, poor self-image, depression, and anxiety due to the lesions’ prominence and appearance. Its direct costs including lost productivity exceed $3 billion annually in the United States. Patients may treat minor cases of acne vulgaris with topical therapies. The most used topical acne medications include retinoids, benzoyl peroxide, topical antibiotics, or a combination of two or all three of these drugs. Moderate to severe acne vulgaris often necessitates the addition of systemic therapies as an adjunct to existing topical regimens. Prescribers use oral antibiotics or hormonal medications to treat moderate to severe acne in conjunction with topical therapies, as tolerated. Isotretinoin is an oral systemic drug used for severe recalcitrant nodular acne. Isotretinoin is given as monotherapy and has a corresponding Risk Evaluation and Mitigation Strategy (REMS) program with which patients must comply due to the drug’s teratogenicity. Several other physical modalities and alternative medicines may be used for acne; however, the data is not robust enough to prioritize their use.

INTRODUCTION

Acne vulgaris is a chronic skin condition characterized by open or closed comedones (bumps) and the development of inflammatory papules, pustules, or nodules.¹ Papules are small, raised bumps; pustules are small, pus-filled bumps; and nodules are larger, solid lesions that extend into the deeper layers of the skin. Acne is among one of the most common skin disorders, frequently affecting adolescents and young adults. In the 2013 Global Burden of Disease study, acne vulgaris ranked second most burdensome skin disease among all skin diseases as measured by disability-adjusted life years.² Experts estimate acne’s prevalence in young adults to be between 35% to more than 90%, with males affected more often than females in this age category.³ Acne’s incidence generally declines with increasing age, and tends to exhibit a female predominance following adolescence, affecting up to 15% of women.⁴

While acne is not associated with mortality, several complications may arise such as hyperpigmentation, scarring, and negative psychosocial effects.³ A variety of treatment options are available for acne vulgaris, both over-the-counter (OTC) and prescription; product selection depends on lesion severity and patient-specific factors. Topical therapies are for milder cases, while systemic therapies are employed in more severe cases, typically in conjunction with topical treatments.

Pathogenesis of Acne

Acne vulgaris is a complex inflammatory disorder affecting the pilosebaceous unit of the skin, which is composed of the hair follicle and sebaceous gland (glands that secrete sebum, an oily substance that keeps skin from drying out).³ Acne’s pathogenesis involves several different host factors that lead to lesion formation. The four main contributing factors associated with acne development include hyperkeratinization of follicles, increased sebum production, Cutibacterium acnes bacteria, and inflammation.³

Increased sebum secretion from sebaceous glands, often stimulated by androgens, serves as a growth medium for C. acnes bacteria. This bacterium has the propensity to activate an immune response that subsequently triggers an inflammatory response. The inflammatory response results in the formation of inflammatory papules and pustules.

Acne vulgaris may have other etiologies aside from the four main biologic factors. Cutaneous lesions can occur by way of mechanical injury or skin trauma because of scrubbing, squeezing, or friction, referred to as acne mechanica.⁵ Additionally, an association exists between psychologic stress and increased acne severity. Genetics is another factor that may contribute to the development of acne. Studies have shown that individuals with close family members who have acne are at increased risk of developing the condition.³

Insulin resistance is also implicated in the formation of acne as it can stimulate androgen production and lead to increased serum levels of insulin-like growth factor-1 (IGF-1). Increased IGF-1 levels are linked to increased facial sebum excretion, which ultimately facilitates acne formation. Androgens contribute significantly in the development of acne as they stimulate the growth and secretory function of sebaceous glands, further increasing sebum production.³

Several dietary elements have been associated with acne, although the evidence is not robust. A reduced glycemic index or a glycemic load diet (i.e., a low carbohydrate diet with reduced intake of processed meats, added sugar, and refined grains) may reduce the quantity and severity of acne lesions by reducing free androgens and IGF-1 levels.⁶ Additionally, omega-3 fatty acids can decrease IGF-1 and inhibit pro-inflammatory leukotriene B₄, which potentially lessens the number of lesions. Conversely, milk and dairy products have been associated with an increase in acne lesions, likely due to their opposite effects on IGF-1 levels.³

In addition to dietary intake, the gut microbiome can impact acne development.⁶ A randomized, placebo-controlled double-blind study of 20 adult patients with acne showed promising results in acne improvements with probiotic supplementation over a 12-week period.⁷ While this preliminary data supports the use of probiotics for acne, more robust data is needed to confirm these findings.

Despite these dietary correlations, the relationship between acne and weight or body mass index (BMI) is uncertain. A large population-based study of about 600,000 adolescents in Israel found that obesity was inversely related to the development of acne.⁸Conversely, a smaller scale case-control study of adolescents with moderate to severe acne found a correlation between lower BMI and lower incidence of acne.⁹ As studies have yielded mixed results, a connection is unclear at this time.

Pretreatment Assessment

Prior to establishing a treatment plan, thorough assessment of the types of acne lesions and severity of those lesions is essential. Additionally, clinicians should consider potential contributing factors such as comedogenic skincare products (i.e., products that have a high likelihood of clogging pores), medications, or endocrine disorders. They should also consider the presence of complications such as scarring, hyperpigmentation, or presence and extent of psychologic distress when establishing treatment regimens and setting treatment goals.¹⁰ Anatomic location of the lesions is important to note as well.¹

Acne vulgaris lesions are either comedonal or papulopustular³:

Comedonal lesions are milder in severity and characterized by closed comedones, also known as “whiteheads,” or open comedones, also known as “blackheads.” Comedonal lesions are non-inflammatory and typically smaller than 5 mm in size, or smaller than the size of a pencil top eraser.
Papulopustular acne has a more inflamed presentation with relatively superficial papules or pustules, although still typically smaller than 5 mm in size.
Nodular acne is a more severe variation of papulopustular acne with deep-seated, inflamed and often tender, large papules or nodules.

While no universally accepted method of assessing acne grade or severity exists, several characteristics may differentiate between mild acne and more severe variants. Mild acne typically has limited skin involvement with scattered, small (less than 5 mm in size) comedonal lesions or inflamed papules. Mild acne also has an absence of near confluent skin involvement (defined as lesions that flow together) and no scarring or large nodules. Many visually prominent comedonal or inflammatory papulopustular lesions are characteristic of moderate to severe acne. Other features indicative of moderate to severe acne include the presence of large nodules, scarring, and involvement of multiple body areas.¹⁰

PAUSE AND PONDER: Since several treatments for acne are available over-the-counter (OTC), what is a reasonable regimen for mild acne using only OTC drugs?

Treatment for Mild Acne

The American Academy of Dermatology published guidelines for the management of acne vulgaris in 2016, and on January 30, 2024, the academy published an update to these guidelines in the form of a systematic review.^1,11 The updated guidelines offer evidence-based recommendations and several good practice statements for the management of acne vulgaris. The guidelines classify recommendations as strong, where the benefits clearly outweigh the risks, or conditional, where the benefits are closely balanced with risks and burden. Conditional recommendations apply to most patients, but the most appropriate action may differ depending on patient or other stakeholder values.¹¹

Topical medications—as monotherapy or in combination—are typically the initial treatment of choice for mild acne.¹¹For mild comedonal acne without inflammatory lesions, treatment with a topical retinoid is an appropriate choice.¹ Mild papulopustular and mixed acne may benefit from either a combination of a topical retinoid and topical antimicrobial or benzoyl peroxide and a topical antibiotic. Combining topical antibiotic treatment with benzoyl peroxide decreases the development of antibiotic resistance to C. acnes and improves treatment outcomes.¹⁰ The 2024 guidelines strongly recommend the following topical therapies for patients with acne based on moderate evidence: benzoyl peroxide, topical retinoids, and topical antibiotics (although not as monotherapy).¹¹

Topical Retinoids

Topical retinoids are routinely the initial treatment choice for mild comedonal acne. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, proliferation (self-multiplication), and differentiation (specialization into specific cell types).¹² In comedonal acne, retinoids normalize follicular hyperkeratosis (excessive development of keratin in hair follicles which result in papules) and prevent formation of the microcomedo, the primary lesion of acne.¹⁰ Table 1 lists the four currently available topical retinoid therapies for acne vulgaris: adapalene, tazarotene, tretinoin, and trifarotene.

Table 1. Topical Retinoids for Acne Vulgaris^10,13

Medication	Usual Dosage	Available Dosage Forms	Common Adverse Effects
Adapalene	Apply to acne lesions once daily in the evening or before bedtime	Cream: 0.1% Gel: 0.1% (OTC), 0.3% Lotion: 0.1%	Local skin irritation: erythema (redness), skin scaling, xerosis (dryness), burning, and pruritus (itching); photosensitivity (light sensitivity)
Tazarotene		Cream: 0.05%, 0.1% Gel: 0.05%, 0.1% Foam: 0.1% Lotion: 0.045%	Local skin irritation: burning and stinging, contact dermatitis, erythema, pruritus, skin discoloration, skin inflammation, application site pain, and xerosis; photosensitivity
Tretinoin		Cream: 0.025% to 0.1% Gel: 0.01% to 0.05% Lotion: 0.05% Microsphere gel: 0.04% to 0.1%	Local skin irritation: peeling, xerosis, burning, stinging, erythema, and pruritus; photosensitivity
Trifarotene		Cream: 0.005%	Application site pruritus, skin irritation, and photosensitivity

OTC, over the counter.

Tretinoin, when used topically, reduces the likelihood of follicular epithelial cells from sticking together, and decreases microcomedone formation. Additionally, it can increase turnover of follicular epithelial cells and stimulates mitotic activity or cell division thereby causing expulsion of comedones.¹⁴ Tretinoin is available in various dosage forms including creams, gels, and lotions. Newer formulations of tretinoin such as microsphere gels release the medication more slowly and are generally less irritating.¹⁰

Patients should apply tretinoin to the affected area once daily at bedtime, 20 minutes following washing and drying of the face. Newer formulations are more stable, allowing patients to use them immediately following cleansing.¹⁴ Adverse effects of topical tretinoin, listed in Table 1, are typically most pronounced in the first month of therapy. Pharmacy teams should instruct patients to apply sunscreen in the morning to minimize photosensitivity (sensitivity to light), and guidelines recommend using sunscreen throughout the course of treatment with topical retinoids.¹

Adapalene is a retinoid-like drug that functions as a modulator of cell differentiation, keratinization (i.e., when the epithelial cells develop a hardened horn-like character), and inflammatory processes.¹⁵Adapalene is available as a cream, gel, and lotion applied topically at bedtime after cleansing. It is the only retinoid available without a prescription. Adapalene has demonstrated similar efficacy and superior tolerability compared to other retinoids.¹⁶

Tazarotene is a retinoid prodrug (i.e., inactive compound that turns into an active drug once metabolized) that reduces the number of inflammatory and non-inflammatory lesions in acne vulgaris.¹⁷ Patients apply tazarotene (a cream, gel, foam, or lotion) to the affected area once daily at bedtime after cleansing. The adverse effect profile is similar to that of other retinoids. While topical retinoid therapy is generally not recommended in pregnancy, this topical acne medication is contraindicated in pregnancy.

Trifarotene is a retinoic acid receptor (RAR) agonist with specific activity at the gamma subtype of RAR. RAR activation causes transcription of several genes that are responsible for cell differentiation and mediation of inflammation.¹⁸It is the first topical retinoid specifically studied in both facial and truncal acne, yielding favorable safety, tolerability, and efficacy data in patients with moderate acne.¹⁹ Trifarotene is available as a cream applied once daily in the evening or before bedtime.

Benzoyl Peroxide

Benzoyl peroxide is a topical oxidizing drug which kills the bacteria on the skin, halts the production of sebum, and breaks down the outermost layer of the skin. It has potential to improve both inflammatory and non-inflammatory acne lesions.²⁰ Benzoyl peroxide is available in a variety of dosage forms including creams, gels, washes, and foams and in several concentrations ranging from 2.5% to 10%, most of which are available OTC. Concentration-dependent irritation, staining, and bleaching of fabric and hair is a limiting factor in treatment with benzoyl peroxide. Pharmacists and technicians should inform patients that staining of towels and pillowcases is common when using this medication.

Irritation from benzoyl peroxide manifests as erythema, scaling, xerosis, or stinging, tightening, or burning sensations.¹⁰ Generally, lower concentrations (i.e., 2.5% to 5%), water-based, and wash-off products have better tolerability, particularly in patients with sensitive skin.¹ Presently, C. acnes shows no resistance to benzoyl peroxide, so addition of this medication to other regimens may further minimize development of antibiotic resistance.

Benzoyl peroxide is optimal for mild papulopustular acne with or without comedonal lesions. Patients may use benzoyl peroxide in conjunction with a retinoid or topical antibiotic, and several combination products are available by prescription only (described in Table 2). If using benzoyl peroxide in combination with tretinoin, patients should apply the medications at different times of the day to avoid oxidation or degradation of the tretinoin product (i.e., use benzoyl peroxide in the morning and tretinoin in the evening). Benzoyl peroxide application timing does not matter when co-administered with the tretinoin microsphere formulation or other retinoids.¹ The guidelines recommend using benzoyl peroxide one to three times daily, however, an increase in adverse effects such as dryness can occur with increased frequency of use. Usually, visible improvement occurs after about three weeks of benzoyl peroxide use, and maximal improvement is apparent after eight to 12 weeks.¹⁰

Table 2. Topical Combination Medications for Acne Vulgaris^10,13

Category	Medication	Usual Dosage
Benzoyl Peroxide and Topical Antibiotic	Benzoyl peroxide 5% / clindamycin 1% gel	Apply twice daily
	Benzoyl peroxide 5% / clindamycin 1.2% gel	Apply once daily in the evening
	Benzoyl peroxide 2.5% / clindamycin 1.2% gel	Apply once daily in the evening
	Benzoyl peroxide 3.75% / clindamycin 1.2% gel	Apply once daily in the evening
	Benzoyl peroxide 5% / erythromycin 3% gel	Apply twice daily
Antimicrobial and Retinoid	Clindamycin 1.2% / tretinoin 0.025% gel	Apply once daily in the evening
	Benzoyl peroxide 2.5% / adapalene 0.1% gel	Apply once daily in the evening
	Benzoyl peroxide 2.5% / adapalene 0.3% gel	Apply once daily in the evening
	Benzoyl peroxide 3% / tretinoin 0.1% cream	Apply once daily in the evening
Antimicrobial, Antibiotic and Retinoid	Benzoyl peroxide 3.1% / clindamycin 1.2% / adapalene 0.15% gel	Apply once daily

Topical Clindamycin

Clindamycin is an antibiotic used topically for acne vulgaris, most often in combination with benzoyl peroxide. The guidelines discourage monotherapy with topical antibiotics due to concerns for antibiotic resistance.¹¹ Clindamycin is available in numerous topical dosage forms including gels, solutions, lotions, foam, and pledgets (small cotton rounds with medication embedded) and comes co-formulated with several retinoid medications.

A meta-analysis comparing different topical treatments for acne demonstrated that gels containing benzoyl peroxide and clindamycin in combination were modestly more effective than benzoyl peroxide alone for the treatment of inflammatory acne lesions, superior to clindamycin alone, and resulted in faster improvement.²¹ Clindamycin is generally well tolerated when used topically, but irritation may occur as with any topical acne medication. Patients apply clindamycin to the affected area twice daily. Topical erythromycin is an alternative to clindamycin; however, reduced efficacy due to antibiotic resistance has limited its use.¹

Salicylic Acid and Azelaic Acid

Several alternative topical medications are available for patients with acne who are unable to tolerate retinoid therapy. Topical salicylic acid is a comedolytic medication (product which resolves papules and prevents formation of new ones) with mild anti-inflammatory properties that works by causing desquamation (shedding) of the horny layer of skin.²² It is available OTC in a variety of different gels, washes, pads, masks, lotions, and solutions. The guidelines conditionally recommend salicylic acid for patients with acne based on low certainty of evidence.¹¹Salicylic acid is typically dosed once daily, however patients may increase to two or three times daily if needed, as tolerated. Skin dryness and peeling may occur from using this medication, especially when used in excess.²³ For patients seeking an OTC resolution for acne, pharmacists can suggest salicylic acid in combination with benzoyl peroxide.

Azelaic acid is an effective treatment for acne due to its antimicrobial and antikeratinizing effects on the follicular epidermis and carries a conditional recommendation based on the guidelines.^24,11 Azelaic acid possesses mild anti-inflammatory properties and can improve acne-induced, post-inflammatory hyperpigmentation.¹⁰ Patients apply this medication to the affected area twice daily, and it comes formulated as a cream, gel, and foam. Studies have shown that azelaic acid’s efficacy is comparable to other topical acne treatments, and it is generally well tolerated. Azelaic acid’s most common adverse effect, as with other topical acne medications, is local skin irritation.^25,26

Alternative Therapies for Resistant Disease

In patients who report insufficient improvement with first line treatments, providers may consider several additional topical options before starting systemic therapy. For comedonal acne, providers may try an alternative concentration of the retinoid therapy if there is room to increase, or switch to another retinoid drug if the current medication is already maximally dosed. For papulopustular acne, providers may change the retinoid medication or add concomitant benzoyl peroxide and/or a topical antibiotic, if desired. Alternative approaches to managing papulopustular acne involve the addition of topical dapsone, clascoterone, or topical minocycline.¹⁰ Table 3 lists antimicrobial therapies and additional alternative topical medications available for the treatment of acne vulgaris.

Table 3. Antimicrobial Therapies and Alternative Topical Medications used for Acne Vulgaris^10,13

Category	Medication	Usual Dosage	Available Dosage Forms	Common Adverse Effects
Antimicrobial	Benzoyl Peroxide	Apply one to three times daily	2.5 to 10% gels, lotions, creams, pads, masks, cleansers, foam (most are OTC)	Local skin irritation
	Clindamycin	Apply twice daily	1% gel, lotion, pledget, solution, foam	Generally well tolerated, skin irritation may occur
	Dapsone	Apply once daily	Gel: 5%, 7,5%	Application site dryness and pruritus
	Erythromycin	Apply twice daily	2% gel, solution, pledget	Generally well tolerated, skin irritation may occur
	Minocycline	Apply once daily 1 hour prior to bed	Foam: 4%	Headache
Topical Androgen Receptor Inhibitor	Clascoterone	Apply twice daily	Cream: 1%	Scaling, dryness, edema, or irritation of skin; HPA axis suppression
Other	Azelaic acid	Apply twice daily	Cream: 20%	Local skin irritation
			Gel: 15%
			Foam: 15%
	Salicylic acid	Apply one to three times daily	0.5 to 2% creams, gels, pads, cleansers, solutions, soaps, pledget, foam (most are OTC)	Local skin irritation including transient stinging, burning, or pruritus; potential for salicylate absorption

HPA, hypothalamic-pituitary-adrenal; OTC, over the counter.

PAUSE AND PONDER: What factors could contribute to the higher prevalence of acne in males during adolescence?

Topical dapsone is an antimicrobial agent that shows modest to moderate efficacy, particularly in the reduction of inflammatory acne lesions in clinical trials.^27,28 While dapsone’s mechanism of action is poorly understood, it is thought to possess both anti-inflammatory and antimicrobial properties. Additionally, dapsone has demonstrated superior efficacy in females as opposed to males.²⁹ Dapsone may be used in combination with benzoyl peroxide, however due to the potential for oxidation, patients must apply the medications at different times. Temporary yellow or orange discoloration of the skin and hair may occur if patients apply dapsone and benzoyl peroxide simultaneously. Patients apply dapsone to the affected area once daily and generally tolerate it well. Unlike with oral dapsone therapy, testing for glucose-6-phosphate dehydrogenase is unnecessary.¹

Clascoterone is a first-in-class topical androgen receptor inhibitor indicated for the treatment of acne vulgaris in individuals aged 12 years and older.³⁰ This medication competes with dihydrotestosterone (DHT) for androgen receptors to block DHT from binding to these receptors. This in turn reduces the transcription of androgen-responsive genes that modulate inflammation and sebum production.³⁰ Two phase 3 randomized clinical trials demonstrated that clascoterone has a similar safety profile to placebo without any downstream systemic androgenic effects.³¹ Patients apply clascoterone to the affected area twice daily. Clascoterone’s most common adverse effects include scaling, dryness, edema, or irritation of skin. Another, more serious potential adverse effect is hypothalamic-pituitary-adrenal axis suppression (i.e., inadequate cortisol production leading to impaired stress response).¹⁰Currently, clascoterone carries a conditional recommendation for the treatment of acne; this is based on a high certainty of evidence, however, also considers cost and access to treatment.¹¹

Treatment for Moderate to Severe Acne

Patients with moderate to severe acne may benefit from topical therapy, but this disease severity often necessitates the addition of systemic medications to achieve optimal outcomes. The guidelines recommend several different oral medications for acne vulgaris including antibiotics, isotretinoin, and hormonal medications, listed in Table 4.¹ Prescribers usually employ systemic therapy in combination with topical medications, but they use oral isotretinoin as monotherapy. Drug selection is based on lesion severity and consideration of patient-specific factors.

Table 4. Systemic Therapies for Acne Vulgaris^10,13

Category	Medication	Usual Dosage	Common Adverse Effects
Tetracycline Antibiotics	Doxycycline	Immediate Release: 50 to 100 mg twice daily or 100 mg once daily Delayed Release: 100 mg every 12 hours for 1 day, then 100 mg once daily Sub-antimicrobial dosing: Immediate Release: 20 mg twice daily Delayed Release: 40 mg once daily	Photosensitivity, GI distress, pseudotumor cerebri; contraindicated in pregnancy and children < 8 years of age
	Minocycline	Immediate Release: 50 or 100 mg daily or twice daily Extended Release: 1 mg/kg/day (round to nearest available strength)	Dizziness, vertigo, serum sickness, drug-induced lupus, skin discoloration, pseudotumor cerebri; contraindicated in pregnancy and children <8 years of age
	Sarecycline	33 to 54 kg: 60 mg once daily 55 to 84 kg: 100 mg once daily 85 to 136 kg: 150 mg once daily	Photosensitivity, GI distress; contraindicated in pregnancy and children <8 years of age
Macrolide Antibiotics	Azithromycin	Pulse dosing due to long drug half-life; 500 mg 1–3 times per week or 4 times monthly was studied, optimal regimen unknown	GI distress
Macrolide Antibiotics	Erythromycin	250 to 500 mg twice daily initially, then decrease to once daily	GI distress
Aldosterone Receptor Antagonists	Spironolactone	50 to 100 mg/day in 1 or 2 equally divided doses	Menstrual irregularity, breast tenderness, minor GI symptoms, orthostatic hypotension, hyperkalemia, dizziness, headaches, fatigue; contraindicated in pregnancy
Oral Retinoids	Isotretinoin	0.5 mg/kg/day, increasing to 1 mg/kg/day in 1 or 2 equally divided doses; total dose 120 to 150 mg/kg over 20 weeks	Dry skin and mucous membranes, visual changes, myalgia, hypertriglyceridemia, elevation of hepatic enzymes; teratogenic (absolutely contraindicated in pregnancy)
Combination Oral Contraceptives	Various estrogen/progestin combinations	One tablet once daily	Nausea, breast tenderness, weight gain, thromboembolic events

GI, gastrointestinal.

Oral Antibiotics

Systemic antibiotics are indicated for moderate to severe inflammatory acne.¹ Antibiotics reduce inflammation by inhibiting the growth of C. acnes bacteria, with some antibiotics also exhibiting direct anti-inflammatory properties.When initiating oral antibiotic therapy for acne, prescribers should limit the duration of treatment to the shortest necessary interval to minimize antibiotic resistance; continuous therapy for three or four months is typically sufficient.³² The guidelines recommend simultaneous use of a topical retinoid with the oral antibiotic. Addition of topical benzoyl peroxide will further limit occurrence of antibiotic resistance.³²

Tetracycline antibiotics are first-line medications for the treatment of acne vulgaris.¹ While other antibiotics may be used when treatment fails or is not tolerated, treatment with non-antibiotic systemic medications (e.g., isotretinoin) is typically considered first.³² Tetracycline antibiotics inhibit protein synthesis by binding the 30S subunit of the bacterial ribosome, and they also possess anti-inflammatory properties.¹Children younger than eight years old and patients who are pregnant cannot use tetracyclines due to the potential for discoloration of developing permanent teeth. Doxycycline, minocycline, and sarecycline are the main tetracyclines used for acne in the United States (U.S.). Providers no longer use tetracycline itself for acne due to tolerability issues, antibiotic resistance, and limited availability.

The guidelines strongly recommend doxycycline for acne vulgaris based on moderate evidence.¹¹ The typical recommended dose of doxycycline for acne is 100 mg twice daily. Patients take delayed release tablets once daily after the initial loading dose.³³ Several studies have also shown that sub-antimicrobial dosing of doxycycline—either 20 mg twice daily or 40 mg once daily of the delayed-release formulation—is an effective strategy for acne vulgaris management.^34-36 This dosing strategy eliminates the drug’s antibacterial action while maintaining its anti-inflammatory effects. Data shows that once daily 40 mg delayed-release doxycycline reduced inflammatory lesions and was better tolerated than doxycycline 100 mg once daily.³⁴ Doxycycline’s most common adverse effects are gastrointestinal complaints, which patients can mitigate by taking the medication with food. Photosensitivity and benign increased intracranial pressure (pseudotumor cerebri) have also been associated with the use of tetracyclines, including doxycycline.³³

Minocycline is a tetracycline antibiotic that the guidelines conditionally recommended for the treatment of acne vulgaris based on moderate evidence.¹¹ Although minocycline is effective, it has been associated with greater toxicity than doxycycline, so it is not usually used first.³⁷ Typical minocycline dosing is 50 mg to 100 mg twice daily, or 1 mg/kg/day of the extended-release formulation. Minocycline may produce vestibular adverse effects such as headache, dizziness and vertigo, serum sickness, and pseudotumor cerebri. According to a systematic review, minocycline is the only tetracycline associated with the development of lupus erythematosus, although the risk is small.³⁷ Photosensitivity may also occur with minocycline but typically to a lesser extent than with doxycycline.³²

Sarecycline is a newer, narrow-spectrum tetracycline antibiotic indicated for inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older.³⁸ The guidelines conditionally recommended this medication based on high certainty evidence.¹¹ A narrow-spectrum antibiotic targets specific types of bacteria, while a broad-spectrum antibiotic is effective against a wide range of bacteria. Using this narrow-spectrum drug reduces the potential for antibiotic resistance and gut microbiome disruption.³² Sarecycline dosing is weight-based ranging from 60 mg to 150 mg once daily.³⁸ Importantly, studies have not established sarecycline’s efficacy beyond 12 weeks or safety beyond 12 months. Sarecycline’s most common adverse effect in clinical trials was nausea.³⁸

Alternative antibiotics for acne vulgaris are reserved for patients who cannot tolerate or don’t respond well to tetracyclines and are not candidates for other systemic therapies.³² Clinical trials have evaluated macrolides—including erythromycin and azithromycin—for acne. A meta-analysis comparing the efficacy of azithromycin to doxycycline demonstrated that azithromycin pulse therapy (i.e., 500 mg one to three times per week or four times monthly) is equivalent to doxycycline 100 mg once or twice daily at 12 weeks in moderate to severe acne vulgaris.³⁹ While some data supports their efficacy, macrolides are rarely used for this indication due to concerns for antibiotic resistance.⁴⁰ Additionally, erythromycin is very poorly tolerated due to significant gastrointestinal adverse effects.

Other antibiotic regimens that may be effective for acne in adults are trimethoprim-sulfamethoxazole 160 mg/800 mg once to twice daily and cephalexin 500 mg twice daily, but data supporting their use is limited.⁴¹ The guidelines discourage using these antibiotics for acne due to increased risk of antibiotic resistance.¹

Topical Antibioitcs

Providers may consider topical minocycline as an alternative topical antibiotic for acne vulgaris in moderate to severe cases. Topical minocycline comes as a 4% foam and is indicated for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older.⁴² Three large clinical trials have shown topical minocycline foam consistently reduces inflammatory acne lesions.^43,44 Patients apply the medication to the affected area at the same time each day at least one hour before bedtime. Pharmacists should inform patients that minocycline foam is well tolerated, with headache being the most notable adverse effect.⁴²

Isotretinoin

Isotretinoin is an oral retinoid that tackles all four major factors in acne pathogenesis: sebum production, follicular hyperkeratinization, inflammation, and C. acnes bacteria. Isotretinoin is U.S. Food and Drug Administration (FDA) approved for the treatment of severe recalcitrant (refractory) nodular acne vulgaris.³²This medication is also a good option for moderate acne resistant to other treatments or for the management of acne that has produced physical scarring or psychosocial distress.¹ Oral isotretinoin is the only medication that can permanently alter the natural course of acne vulgaris, and has the potential to induce long-term remission.³² Most patients experience long-term improvement in acne severity after just one course of isotretinoin. Additionally, continued improvement may occur for several months following completion of the treatment course, so patients must wait at least five months before considering additional isotretinoin therapy.⁴⁵

Patients take isotretinoin as monotherapy over the course of several weeks. Dosing is weight-based starting at 0.5 mg/kg/day in two divided doses, then titrated up to 1 mg/kg/day after the first month. The typical treatment duration is 15 to 20 weeks or until the total nodule count decreases by more than 70%, whichever occurs first.⁴⁶ Taking the medication with food improves absorption (an important counseling point). Isotretinoin is contraindicated in pregnancy due to its teratogenicity (causes birth defects), but it is unclear whether teratogenic effects occur in sperm from males using isotretinoin.⁴⁷ All patients who are prescribed the medication, prescribing providers, and pharmacies who dispense isotretinoin must enroll in the iPLEDGE REMS to receive the medication. Pharmacy teams play an integral part in ensuring patients can safely obtain this medication. They must verify that both the patient and provider are enrolled, obtain a Risk Management Authorization (RMA) number prior to filling and dispensing each prescription, and that no more than a 30-day supply is dispensed. Additionally, upon authorization, the iPLEDGE REMS website provides a “do not dispense to patient after” date. It is calculated as 30 days after the office visit for patients who cannot get pregnant, and seven days from the documented negative pregnancy test for patients who can.

Isotretinoin is associated with several potential adverse effects including dry skin and mucous membranes, visual changes, and myalgia. Additionally, patients, particularly those with severe disease, may see an initial transient worsening of acne that requires adjustment to therapy.⁴⁵ Isotretinoin is known to cause hyperlipidemia and elevation of hepatic transaminases (liver enzymes) necessitating lab monitoring.³² Some research suggests a possible link between depression and suicidal ideation, but the data is inadequate to establish causality at this time.^48,49 Researchers have also suggested a link between isotretinoin and inflammatory bowel disease, but several large cohort studies have not confirmed this.^50-52

PAUSE AND PONDER: What would be the best course of action for a pregnant patient with acne?

Oral Hormonal Therapies

Combination oral contraceptives (COC) and/or spironolactone may be reasonable therapeutic options for patients with acne vulgaris assigned female sex at birth. Both therapies carry a conditional recommendation for use in acne based on moderate evidence.¹¹ These hormonal therapies work by reducing the androgenic effects on sebaceous glands, reducing sebum production. This can ultimately diminish comedone development and minimize C. acnes bacteria growth.³²

COCs containing an estrogen and progestin are effective therapies for acne vulgaris in female patients. Although most progestins in oral contraceptives have androgenic properties, all low-dose COCs are estrogen dominant and produce an overall antiandrogenic effect.³² The four COCs with an FDA approval for the treatment of acne vulgaris are

drospirenone 3 mg/ethinyl estradiol 0.02 mg
drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate calcium 0.451 mg
norethindrone acetate/ethinyl estradiol/ferrous fumarate (triphasic formulation, meaning dose differs by the week)
norgestimate/ethinyl estradiol (triphasic formulation)

These are all approved for patients with acne vulgaris who also desire contraception.¹³

COCs for acne are not for use in patients who are younger than 14 years of age or within the first two years of starting menses unless it is clinically warranted.¹Other contraindications to COCs exist, including smokers aged 35 and older and patients with select cardiovascular and gastrointestinal comorbidities.¹¹ COCs may be used in combination with other oral acne medications, including the tetracyclines and spironolactone.¹ All COCs are associated with cardiovascular risks including thromboembolism and myocardial infarction, specifically in smokers. Additionally, they carry a potential risk of breast cancer and cervical cancer.¹³Providers do not use progestin-only contraceptives for acne vulgaris as their androgenic properties may exacerbate acne.³²

Spironolactone is an aldosterone receptor antagonist with potent antiandrogen activity. It decreases testosterone production and competitively inhibits binding of testosterone and DHT to androgen receptors. Spironolactone may also inhibit 5-alpha-reductase (the enzyme that converts testosterone to DHT) and increase steroid hormone binding globulin (a protein that binds to estrogens and androgens).¹While spironolactone is not FDA approved for acne, clinicians often use it off-label based on available evidence and expert opinion.^53-55 When used for acne, spironolactone is dosed at 50 mg to 100 mg in one or two equally divided doses. Patients generally tolerate it well, and the most common adverse effects include diuresis (increased urination), menstrual irregularities, breast tenderness, breast enlargement, fatigue, headache, and dizziness.¹ It is also important to note that spironolactone is a potassium-sparing diuretic and hyperkalemia (high potassium levels) may occur when given at high doses or in patients with comorbidities such as renal insufficiency or severe heart failure. Hyperkalemia can be serious, but young, healthy patients taking spironolactone for acne do not appear to be at significant risk for hyperkalemia and don’t require monitoring.^11,32

Rare, Severe Acne Variants

Acne Fulminans

Acne fulminans is a rare form of acne vulgaris characterized by the sudden development of large, inflammatory nodules and friable (fragile) plaques with erosions, ulcers, and hemorrhagic crusts. This may occur with or without systemic symptoms such as fever, malaise, bone pain, and arthralgias.³ These lesions typically present on the trunk; however, they may occur elsewhere. Isotretinoin can trigger acne fulminans, but some cases are idiopathic (no known cause). Acne fulminans typically occurs in adolescent males with preexisting acne vulgaris.³

Treatment for acne fulminans involves using oral corticosteroids, usually prednisone 0.5 mg to 1 mg/kg/day, in combination with isotretinoin. If isotretinoin precipitated acne fulminans, prescribers must stop this medication and proceed with corticosteroid monotherapy for four weeks in patients with systemic symptoms and for two weeks for patients without systemic symptoms. When acne fulminans resolves, patients may restart isotretinoin in conjunction with the oral corticosteroid for at least four weeks before gradually titrating isotretinoin up as tolerated and reducing the corticosteroid dose. Providers may consider combination therapy with oral corticosteroids and tetracyclines for acne fulminans, but it is less effective.³²

Acne Conglobata

Acne conglobata is a severe form of nodular acne that primarily affects males. Large draining lesions, sinus tracts (linear, burrowing lesions resulting when multiple nodules merge), and severe scarring are characteristic of acne conglobata. Unlike acne fulminans, acne conglobata is not associated with systemic symptoms.³The recommended treatment is oral isotretinoin, but isotretinoin may also occasionally cause severe flares at the start of therapy. Similar to the treatment for acne fulminans, low initial doses of isotretinoin (0.5 mg/kg per day or less) with oral corticosteroids before or during isotretinoin therapy are usually required.³² Intralesional glucocorticoid injections with triamcinolone acetonide have demonstrated efficacy as an adjunct treatment for severe nodular acne lesions.^1,11Additionally, tetracycline antibiotics have been used for severe nodular acne and may play a role in the treatment of acne conglobata, but they cannot be combined with isotretinoin due to the increased risk of pseudotumor cerebri.⁵⁶ Case reports supporting the use of tumor necrosis factor-alpha inhibitors (i.e., etanercept, adalimumab, and infliximab) have been documented, but more research is needed.^57-59

Physical Modalities and Complementary and Alternative Medicine

While various physical modalities have been employed to treat acne vulgaris, limited evidence supports these approaches in the peer-reviewed medical literature.¹ Comedeo extraction performed by a professional using pressure and excision when necessary to physically remove comedones may be beneficial in resistant cases and is often used in practice. Use of topical tretinoin cream for four to six weeks prior to extraction may be advantageous.²³

Several studies suggest that chemical peels may improve acne mildly, particularly in patients with non-inflammatory comedonal lesions.^60-62 However, more large-scale, high-quality double-blinded placebo-controlled trials are needed. Additionally, evidence suggests the need for multiple treatments, and the results may not be long-lasting.^23,60 Most chemical peels contain glycolic acid or salicylic acid.¹Patients who are taking isotretinoin are not candidates for a chemical peel due to the increased potential for irritation. Pharmacists should counsel patients using topical retinoids to pause therapy for several days prior to receiving a chemical peel.²³

Microdermabrasion is a non-invasive superficial peeling modality in which abrasive crystals are propelled onto the skin and subsequently suctioned with a vacuum device, resulting in exfoliation of the outermost layer of the epidermis.²³ A pilot study conducted in a cohort of 24 patients supports the use of microdermabrasion for acne, but these patients continued to take other acne medications throughout the study.⁶³High-quality evidence to support the effectiveness of microdermabrasion for acne is lacking.

Laser and light-based therapies have been used to treat acne, but additional studies are needed to evaluate their efficacy.⁶⁴ Dermatologists have used intense pulsed light, broad-spectrum continuous-wave visible light (i.e., blue light and red light), photodynamic therapy, photopneumatic technology, and laser sources such as potassium titanyl phosphate laser, pulsed dye laser, and infrared lasers.²³The guidelines conditionally recommend against adding pneumatic broadband light to adapalene 0.3% gel based on low certainty evidence, however available evidence is insufficient to establish recommendations for other light-based therapies.¹¹

Photodynamic therapy shows the most promise compared to the other laser and light therapies.⁶⁵With this modality, the dermatologist applies a photosensitizer, such as aminolevulinic acid, to the affected skin for 15 minutes to three hours.¹ The skin then absorbs the photosensitizer where sebocytes (sebum-producing epithelial cells) absorb it preferentially. Subsequently, a laser or light device activates the photosensitizer that generates singlet oxygen species, damaging the sebaceous glands and reducing C. acnes bacteria. While this treatment has great potential, additional research is necessary to determine the optimal photosensitizer, incubation time, and light source.¹

Complementary and Alternative Medicine

Tea tree oil, also known as melaleuca oil, is an essential oil produced by steaming the leaves of the Australian tea tree. Tea tree oil has been used for a variety of conditions and possesses both antimicrobial and anti-inflammatory properties.⁶⁶ Two clinical trials assessed tea tree oil’s effectiveness in acne vulgaris.^67,68 A placebo-controlled trial determined that topical 5% tea tree oil is effective for mild to moderate acne vulgaris.⁶⁷ A comparator trial compared tea tree oil to benzoyl peroxide for acne and demonstrated that tea tree oil is comparable to benzoyl peroxide with better tolerability but slower onset of action.⁶⁸ Pharmacists should note that tea tree oil may be a good option for patients seeking a more natural remedy for acne. While data supports its use, the guidelines state that available evidence is insufficient to develop a recommendation on the use of tea tree oil for acne.¹¹

Alpha hydroxy acids, such as glycolic acid and lactic acid, are weak organic acids that induce skin peeling to improve acne and hyperpigmentation among other dermatologic conditions. They are available over the counter in a variety of dosage forms (e.g., creams, washes, lotions) and are used in higher concentrations for in-office chemical peels.²³ Some preliminary evidence supports the use of alpha hydroxy acids for acne; however, they are thought to confer the most benefit when used synergistically as a component of a comprehensive acne regimen.⁶⁹

While conclusive studies supporting safety and efficacy are lacking, several marketed devices claim to improve acne using heat. These devices produce a pulse of heat directly to the lesion, which is thought to kill any C. acnes bacteria present and produce an anti-inflammatory effect. The FDA has cleared multiple devices for this purpose, meaning they have gone through a review process, but medical devices of this type do not undergo the rigorous FDA approval process that requires clinical trials.^{23, 70}

Conclusion

A variety of treatment options for acne vulgaris are available, and treatment selection is based on lesion severity and patient preference. Clinicians treat mild acne with topical medications, several of which are available OTC. Patients seeking OTC solutions may consider benzoyl peroxide, salicylic acid, or adapalene, and tea tree oil is an option for those seeking a more natural remedy. Topical therapies are often employed first for milder acne, however they are often beneficial as part of the treatment plan in more severe cases as well. Systemic medications such as antibiotics, hormonal medications, and isotretinoin treat moderate to severe acne. Pharmacy teams should ensure patients are aware of the potential for gastrointestinal symptoms with antibiotics and isotretinoin’s teratogenicity, among other potential adverse effects. Oral corticosteroids are appropriate for very severe cases involving relatively rare acne variants. Several other alternative therapies and physical modalities may be employed as part of the regimen for acne vulgaris, but more research is necessary to assess the safety and efficacy of these options.

Acne Vulgaris Pathogenesis and Treatment

Pharmacist Post-test

After completing this continuing education activity, pharmacists will be able to:

1) Describe the pathogenesis of acne, including the potential role of diet
2) Outline topical and systemic pharmacologic therapies used to treat acne
3) Identify physical modalities with utility in treating acne
4) Review available evidence supporting complementary and alternative medicine use for acne

1. What are the four main contributing factors implicated in the development of acne vulgaris?
A. Hypokeratinization of follicles, increased sebum production, C. acnes bacteria, and inflammation
B. Hyperkeratinization of follicles, increased sebum production, C. acnes bacteria, and inflammation
C. Hyperkeratinization of follicles, reduced sebum production, C. acnes bacteria, and inflammation

2. What dietary element is associated with an increase in acne lesions?
A. Dairy products
B. Omega-3-fatty acids
C. High fat diet

3. Jessica is a 14-year-old patient who presents with bothersome acne. She has primarily white heads and black heads and does not appear to have any inflammatory nodules. Which topical therapy would be MOST appropriate to start with as monotherapy?
A. Benzoyl Peroxide
B. Clindamycin
C. Tretinoin

4. What is the purpose of using benzoyl peroxide in addition to topical antibiotics for acne?
A. To reduce skin irritation
B. To improve the appearance of scarring
C. To reduce antibiotic resistance to C. acnes

5. Which topical retinoid is available over-the-counter without a prescription?
A. Adapalene
B. Tretinoin
C. Tazarotene

6. Which systemic medication is usually used as monotherapy for severe acne?
A. Tetracycline
B. Spironolactone
C. Isotretinoin

7. Matthew is a 17-year-old male who was taking minocycline for his moderate to severe acne. He experienced significant gastrointestinal symptoms, so he stopped taking it. What is the MOST reasonable option to consider next?
A. Doxycycline
B. Spironolactone
C. Isotretinoin

8. Which laser/light-based therapy shows the most promise for acne treatment?
A. Photodynamic therapy
B. Photopneumatic technology
C. Infrared lasers

9. Which of the following BEST describes acne conglobata?
A. A rare form of acne vulgaris characterized by sudden development of large, inflammatory nodules, and friable plaques
B. A severe form of nodular acne characterized by large draining lesions, sinus tracts, and severe scarring
C. A severe variation of papulopustular acne with deep-seated, inflamed, and often tender, large papules or nodules

10. Which alternative therapy originates from a plant source in Australia?
A. Tea tree oil
B. Glycolic acid
C. Lactic acid

Acne Vulgaris Pathogenesis and Treatment

Pharmacy Technician Post-test

After completing this continuing education activity, pharmacy technicians will be able to:

2. What dietary element is associated with an increase in acne lesions?
A. Dairy products
B. Omega-3-fatty acids
C. High fat diet

3. Which topical acne treatment can cause bleaching of fabric and hair?
A. Tretinoin
B. Benzoyl peroxide
C. Adapalene

4. Which class of antibiotics is a first-line treatment for moderate to severe acne?
A. Penicillins (e.g., amoxicillin, ampicillin, dicloxacillin)
B. Tetracyclines (e.g., doxycycline, minocycline, sarecycline)
C. Macrolides (e.g., azithromycin, erythromycin)

5. Which topical retinoid is available over-the-counter without a prescription?
A. Adapalene
B. Tretinoin
C. Tazarotene

6. Which of the following is a non-invasive superficial peeling modality in which abrasive crystals are propelled onto the skin and subsequently suctioned within a vacuum device?
A. Photodynamic therapy
B. Chemical peel
C. Microdermabrasion

7. IPLEDGE is a Risk Evaluation and Mitigation Strategy (REMS) used for which acne medication, meaning this medication cannot be dispensed without the provider, patient, and pharmacy registering with this program?
A. Sarecycline
B. Isotretinoin
C. Trifarotene

8. Which laser/light-based therapy shows the most promise for acne treatment?
A. Photodynamic therapy
B. Photopneumatic technology
C. Infrared lasers

9. Which medications for moderate to severe acne can only be used to treat acne in individuals assigned female sex at birth?
A. Combined oral contraceptives and spironolactone
B. Combined oral contraceptives and isotretinoin
C. Spironolactone and isotretinoin

10. Which alternative therapy originates from a plant source in Australia?
A. Tea tree oil
B. Glycolic acid
C. Lactic acid

References

1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris [published correction appears in J Am Acad Dermatol. 2020;82(6):1576]. J Am Acad Dermatol. 2016;74(5):945-73. e33. doi: 10.1016/j.jaad.2015.12.037
2. Karimkhani C, Dellavalle RP, Coffeng LE, et al. Global Skin Disease Morbidity and Mortality: An Update From the Global Burden of Disease Study 2013. JAMA Dermatol. 2017;153(5):406-412. doi:10.1001/jamadermatol.2016.5538
3. Thiboutot D, Zaenglein AL. Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris. In: UpToDate, Dellavalle RP, Levy ML, Owen C (Eds), Wolters Kluwer. Updated March 29, 2022. Accessed January 15, 2024.
4. Skin conditions by the numbers. American Academy of Dermatology. Accessed January 22, 2024. https://www.aad.org/media/stats-numbers
5. Dreno B, Bettoli V, Perez M, Bouloc A, Ochsendorf F. Cutaneous lesions caused by mechanical injury. Eur J Dermatol. 2015;25(2):114-121. doi:10.1684/ejd.2014.2502
6. Baldwin H, Tan J. Effects of Diet on Acne and Its Response to Treatment. Am J Clin Dermatol. 2021;22(1):55-65. doi:10.1007/s40257-020-00542-y
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Overview of the Medicare Prescription Payment Plan

Figure 1 illustrates the basic process for patients who choose to participate in M3P.

Table 1. Anticipated M3P Claims Messaging Information

Distribution of M3P responsibilities

Table 2. Plan M3P Responsibilities4, 5

Monthly invoice calculations and members most likely to benefit from participating in the M3P

M3P Resources

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Table 2. Plan M3P Responsibilities^{4, 5}