INTRODUCTION

Practitioners in all healthcare settings need to understand and respect gender diversity. Pharmacists and pharmacy technicians can play a pivotal role in gender-affirming care by using inclusive language and developing comprehensive knowledge of pharmacologic interventions. The scope of gender affirming care ranges from puberty suppression to gender-affirming surgeries to align physical appearance with gender identity. Gender dysphoria is a very serious condition among transgender individuals that can lead to depression and suicide. Gender dysphoria is not solely internally driven and can be exacerbated by external stressors/stigma. This includes external aspects of experience such as distress associated with misgendering and social norms, social isolation, transphobia, etc.^1,2 It may be treated with hormone therapy and can require lifelong treatment. Healthcare professionals in the pharmacy setting can help these patients by creating a supportive environment that promotes adherence to their treatment. The SIDEBAR provides definitions for frequently used terms in transgender care.

SIDEBAR: Terminology^1-6

• Gender expression: External manifestations of gender, expressed through one’s behavior, body characteristics, clothing, haircut, name, pronouns, or voice. Typically, transgender people seek to make their gender expression align with their gender identity, rather than their assigned gender.
• Gender role: Behaviors, attitudes, and personality traits that a society (in a given culture and historical period) assigns as masculine or feminine and/or that society associates with or considers typical of the social role of men or women
• Gender identity/experienced gender: One’s internal, deeply held sense of gender. For transgender people, gender identity does not match their sex assigned at birth. Most people have a gender identity of male or female. For some people, gender identity does not fit neatly into one of those two choices (e.g., nonbinary). Unlike gender expression, gender identity is invisible to others.
• Sex: The best-known attributes include sex-determining genes, sex chromosomes, gonads, sex hormones, internal and external genitalia, and secondary sex characteristics.
• Sex assigned at birth: Sex assigned at birth, usually based on genital anatomy. AFAB refers to "assigned female at birth," and AMAB to "assigned male at birth."
• Transgender (also TGD, trans): An umbrella term for people whose gender identity and/or gender expression differs from what is typically associated with their sex assigned at birth. Not all transgender individuals seek treatment.
• Cisgender: A term for people whose gender identity and/or gender expression is aligned with what is typically associated with their sex assigned at birth.
• Gender dysphoria: The distress experienced when one’s gender identity and assigned gender are incongruent, often worsened by external factors like misgendering, social norms, isolation, and transphobia. Not all transgender people experience gender dysphoria; being transgender on its own is not a medical condition.
• Transition: The process during which transgender people change their physical, social, and/or legal characteristics consistent with their affirmed gender identity. Transgender individuals may initially transition socially and postpone medical transition. This is especially true for prepubertal children.
• Transgender male (also: trans man, female-to-male): Individuals assigned female at birth but who identify and live as men.
• Transgender woman (also: trans woman, male-to female, transgender female): Individuals assigned male at birth but who identify and live as women.
• Non-binary: An adjective describing a person who does not identify exclusively as a male or a female. Non-binary people may identify as being both male and female, somewhere in between, or as falling completely outside these categories. While many also identify as transgender, not all non-binary people do.
• Embodiment goals: Body qualities/characteristics that a patient wishes to have (e.g. shape, feeling, behavior of body).

Guidelines

The World Professional Association for Transgender Health (WPATH) publishes the Standards of Care for the Health of Transgender and Gender Diverse People (SOC),⁷ which is the main guideline used internationally for transgender health. This continuing education activity is based on SOC Version 8.

The Endocrine Society develops the Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline.³ These guidelines establish a framework for the appropriate treatment of individuals and standardize terminology to be used by healthcare professionals. This activity cites these guidelines as well.

Inclusive Language

Everyday language often revolves around the concept of two genders and one sexuality, potentially overlooking diverse identities. Using gender-inclusive language demonstrates respect and acknowledgment of all gender identities while eliminating assumptions. Using they/them pronouns instead of he/his or she/her when unsure of someone's pronouns is best.⁶ Healthcare professionals can demonstrate inclusivity by introducing themselves with their own pronouns and asking patients how they prefer to be addressed. Common pronouns include she/her/hers, he/him/his, and they/them/theirs..⁶ Healthcare professionals should avoid stating that a person is transgender to others unless that is how the person identifies and is comfortable with sharing that information.⁶ Another suggestion is saying “feel free to bring your spouse or partner” instead of “feel free to bring your husband or wife.”⁶

PAUSE AND PONDER: A fellow colleague consistently misgenders a transgender patient despite being corrected. How would you address this behavior while promoting inclusivity and respect in the pharmacy setting?

Physiology

Puberty is the process of an adolescent becoming capable of reproduction. This process involves the hypothalamic-pituitary-gonadal axis. The first biologic sign of puberty is an increase in endogenous gonadotropin hormone-releasing hormone (GnRH).⁷ GnRH produced by the hypothalamus causes the pituitary gland to secrete gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH stimulate gonads to produce sex hormones.⁸ Table 1 compares puberty in individuals with ovaries and those with testes.

Table 1. Patterns of Typical Puberty⁷

ADULTS

Feminizing Pharmacology

The goals of feminizing pharmacology care are the development of female secondary sex characteristics and the minimization of male secondary sex characteristics. Treatments include externally dosed estrogens and antiandrogens. The selection of therapy should include a patient-specific evaluation of patient goals, medical conditions, medication risk/benefit, and economics.⁷

Estrogen promotes feminine features such as breast growth. Antiandrogens diminish masculine features by reducing endogenous testosterone. Examples of antiandrogens include spironolactone, cyproterone acetate, GnRH agonists, and 5-alpha reductase inhibitors.

Estrogen

In gender-affirming care, estrogen (or 17-beta estradiol) used for feminizing treatment is chemically identical to estrogen produced by human ovaries.^3,7 Multiple dosing formulations exist including oral tablets, topical patches, intramuscular injections, and topical gels/sprays. A major safety concern for anyone using exogenous estrogen is the increased risk of thromboembolic events. 17-beta estradiol is generally preferred over synthetic estrogens for the ease of monitoring serum levels and its lower risk of thromboembolic events. For those older than 45 years and those at a higher risk of venous thromboembolism (VTE), the guidelines recommend transdermal formulations. Cardiovascular screening is essential to identify patients at higher VTE risk. Due to multiple Boxed Warnings in the product labeling and potentially significant adverse events, providers should use caution and consider the risks and benefits of estrogen therapy.^3,7

The desired effects of exogenous estrogen include breast development, redistribution of facial and subcutaneous fat, reduction of muscle mass, reduction of body hair, and reversal of scalp hair loss. Exogenous estrogen will not alter voice or height in adults. Table 2 describes available estrogens used in gender-affirming care.^3,7

Table 2. Estradiol for GAHT⁹

Antiandrogens

Antiandrogens, listed in Table 3, can reduce endogenous testosterone levels or its activity and are usually used in combination with estrogen for feminizing effects. While antiandrogens may be employed as monotherapy, combination treatment can help minimize the amount of estrogen necessary for gender-affirming effects and therefore reduce the estrogen-associated risks. General adverse effects of antiandrogen monotherapy may include hot flashes, low mood or energy, and bone loss when used long term.⁷

Table 3. Antiandrogens for GAHT^10-13

Spironolactone is a potassium-sparing diuretic that has many therapeutic uses including in heart failure and hypertension. Spironolactone is also an aldosterone receptor antagonist that can cause positive effects, such as gynecomastia (an increase in breast gland tissue) for transgender women. Gynecomastia is dose and duration dependent, occurring in approximately 10% of patients. The diuretic and antihypertensive effects may become apparent within two to three weeks potentially resulting in excess urination and low blood pressure.^3,14

GnRH agonists (histrelin, leuprolide) work by continuously activating the pituitary gland to make more LH and FSH. This overactivation eventually suppresses sex steroid production. Out of pocket costs for these medications can range anywhere from $10,000 to $50,000 for three months, thereby significantly limiting their use.¹⁶

WPATH does not regularly recommend other drugs like 5-alpha reductase inhibitors, finasteride or dutasteride, as data supporting use in the transgender population is sparse.⁷

Cyproterone acetate is a synthetic progestin that inhibits testosterone synthesis and action. This medication is not approved in the United States but may be used elsewhere.³

PAUSE AND PONDER: A transgender patient presents with concerns about the different formulations of estrogen available for feminizing treatment. How would you explain the advantages and disadvantages of each formulation?

Masculinizing Pharmacology

The goals of masculinizing treatment are the development of male secondary sex characteristics and the minimization of female secondary sex characteristics. Masculinizing GAHT typically consists of testosterone.

Testosterone

Testosterone treatment in transgender patients is used in the same way that it is used for hypogonadism in cisgender male patients. Table 4 illustrates the various testosterone formulations in transgender care, including intramuscular, transdermal, and implantable options. Intramuscular injections may be preferred due to available clinical data, efficacy, patient satisfaction, and low levels of injection pain and local irritation relative to subcutaneous injections. Prescribers and patients should not interchange products without considering pharmacodynamic differences.^7,16

Positive effects of masculinizing hormones include irreversible deepening of voice, increased body/facial hair, and increased lean muscle mass. Patients and care teams should know that masculine hormone therapy will not reverse previous feminine features such as breast tissue. Achieving physiological testosterone levels will usually suppress menses. If testosterone monotherapy doesn’t suppress menses, additional therapies can be used including progestins, GnRH agonists, and aromatase inhibitors. Patients may continue testosterone therapy for life unless medically contraindicated.¹⁶

Table 4. Testosterone Formulations for GAHT ¹⁷

CHILDREN

GAHT is not recommended in children who have not begun endogenous puberty. Healthcare providers should take a non-pharmacologic approach instead for pre-pubertal individuals, including psychosocial gender-affirming care. Patients should continue gender exploration regardless of social transition.⁷

ADOLESCENTS

GAHT’s goal in adolescents is pubertal suppression. Halting progression of puberty allows adolescents to explore gender identity and embodiment goals. Although suppression is reversible, the treatment team should discuss fertility preservation before starting supression.⁷ Current timing and readiness estimates are as follows: pubertal suppression at 12 years old, GAHT at 16 years old, and surgery at 18 years old.

Pubertal Suppression Pharmacology

Healthcare providers employ Tanner staging to track children’s development during puberty. It outlines five specific stages for the physical changes during this period, including genital, breast, and pubic hair development. Patients should reach Tanner Stage 2 before initiating pubertal suppression. In Tanner Stage 2, individuals who are assigned female at birth would experience breast budding while those who are assigned male at birth would experience external genitalia enlargement.⁶ Menstrual suppression is recommended for patients assigned female at birth with gender incongruence, regardless of testosterone therapy.⁷

Pharmacologic Agents

Gonadotropin-Releasing Hormone (GnRH) Agonists

GnRH agonists cause partial regression of secondary sex characteristics and inhibit physical functions, such as menses and erections, by decreasing concentrations of gonadotropin and sex steroid hormones. Supraphysiological doses of sex steroids are not needed with GnRH agonists.⁷

Short-term hypertension is an important counseling point. Individuals who are older than 14 years also have a long-term risk of poor bone health because of the lack of exposure to adequate levels of sex steroid hormone levels. Sex steroid hormone therapy, however, induces rapid recovery of bone mineralization rate.⁶

For feminizing therapy, patients should continue puberty blocking until gonadectomy. Masculinizing pharmacology is covered in the following Hormone Therapy section. If patients have functioning uterus and ovaries, health care providers should counsel on potential breakthrough menstrual bleeding two to three weeks after GnRH agonist initiation.

Progestins

Oral or injection depot progestins are recommended if GnRH agonists are unavailable or cost-prohibitive.⁷

Patients can also receive these progestins if they seek menstrual suppression only⁷:

• Oral progestin-only pills (contraceptive and non-contraceptive options)
• Medroxyprogesterone injection (e.g. Depo-Provera)
• Levonorgestrel intrauterine device (e.g. Mirena, Liletta, Kyleena, Skyla)
• Etonogestrel implant (e.g. Nexplanon)

If a patient continues to have menstrual bleeding after taking progestin and/or is seeking a contraceptive, healthcare providers can consider a combination progestin-estrogen product for amenorrhea and counsel on possible breast development. Combined formulations include oral contraceptive pills, transdermal patches, and vaginal rings. Note that increased breakthrough bleeding is associated with lower dose ethinyl estradiol in combined oral contraceptives.⁷

Hormone Therapy (HT)

The patient’s health care professionals will need to measure hormone levels during gender-affirming treatment. The purpose is to ensure that endogenous sex steroids are falling and the sex steroids administered to the patient stay at appropriate levels. Appropriate levels are determined by (1) the patient’s treatment goals and (2) the patient’s Tanner stage. Timing of pubertal suppression determines sex steroid HT regimen, as shown in Table 5.⁷

Table 5. Sex Steroid Hormone Therapy Regimen Based on GnRH Agonist Treatment Timing⁷

WPATH suggests 12 months as sufficient time for psychological adaptations to physical changes due to GAHT. Healthcare providers should monitor sex steroid levels every three months during the first year of HT or with dose changes. Once the prescriber titrates the patient’s dose to the adult maintenance dose, monitoring one to two times annually is sufficient. As GAHT can activate the hypothalamic-pituitary-gonadal axis, prescribers may need to add a GnRH agonist as adjunctive therapy after GAHT initiation to avoid development of characteristics associated with the patient’s sex assigned at birth.⁷

For masculinizing GAHT, testosterone monotherapy at physiologic doses is typically sufficient to decrease estrogen secretion by the ovaries. Injection, transdermal, and subcutaneous pellets are available androgen formulations. Key counseling points include the possibility of developing androgenic acne or sexual dysfunction.

Patients on GnRH agonists should continue them until they reach maintenance testosterone level. If the patient was not on a GnRH agonist as an adolescent, then no concomitant GnRH agonist is needed. While testosterone usually suppresses menstruation in the first six months of therapy, healthcare providers should make sure to counsel adolescents on possible pregnancy despite amenorrhea because they can still ovulate.⁷

NON-PHARMACOLOGIC INTERVENTIONS

Chest Binders

Chest binding refers to compressing breast tissue to achieve a flatter chest appearance. Research indicates that up to 87% of individuals identifying as transgender males have tried chest binding.⁶ Various methods used for binding include commercial binders, sports bras, layering clothes, elastics, and bandages.⁷

Healthcare providers play a crucial role by making patients aware of chest binding’s potential advantages and risks. Transgender men who bind often report benefits such as increased comfort, enhanced safety, and reduced instances of misgendering.⁷

Negative physical impacts of chest binding include back or chest pain, difficulty breathing, and feeling overheated.⁷ Severe health issues like skin or respiratory infections and rib fractures, which are rare, have been linked to adult chest binding.⁶ Providers can lower the risk by counseling patients on safe binding methods, like binders specifically designed for gender-diverse individuals, to lessen the likelihood of serious health complications. Meanwhile, patients should avoid unsafe methods like duct tape, ace wraps, or plastic wrap due to their potential to constrict blood flow, harm the skin, and restrict breathing.⁶ If negative health effects occur, seeking guidance from medical professionals experienced with transgender and gender-diverse patients is sensible.⁷

Tucking

Genital tucking involves positioning the penis and testes to minimize the visibility of genital bulges.⁷ This can be done by tucking the penis and testes between the legs or placing the testes inside the inguinal canal while pulling the penis back between the legs.⁷ Underwear or specialized garments called gaffs are commonly used to keep the genitals in place.⁷

Research on the risks and advantages of tucking in adults is limited, and no studies conducted specifically address youth.⁶ Previous research has highlighted that snug undergarments might lead to reduced sperm concentration and motility. Moreover, higher scrotal temperatures due to tucking might theoretically impact sperm production and fertility.⁷ However, no conclusive evidence confirms these negative effects. More data is needed to understand the risks and benefits of tucking.

Voice Therapy

Hormone treatment for transgender and gender diverse (TGD) individuals has potential effects on voice and communication. While estrogen treatment does not usually cause measurable voice changes, testosterone treatment can lead to desired shifts in voice pitch and male attributions but may also result in undesired outcomes.⁷

Research indicates that some TGD individuals experience positive effects from testosterone, such as lowered voice pitch and increased satisfaction, aligning with their gender identity. However, a significant portion may face challenges like insufficient pitch changes, vocal quality issues, limitations in singing range, and vocal instability post-treatment.^7,18 A meta-analysis examined about 600 patients across 19 studies to determine the effects of at least one year of testosterone therapy. The patients were all at least 18 years old, with an average age of 35 years. According to the results, approximately 21% of participants did not reach the expected normative frequencies associated with cisgender males. Additionally, a similar percentage reported incomplete alignment between their voice and gender identity, experiencing voice-related challenges or incongruence. Furthermore, 16% of individuals undergoing testosterone therapy expressed dissatisfaction with the changes in their voice.¹⁸

It's essential to provide accurate counseling beforehand to establish realistic expectations and avoid potential disappointment. Referral to voice and communication specialists can address concerns through tailored voice training and assisting those dissatisfied with outcomes or lacking access to hormone treatment.⁷

Electrolysis And Laser Hair Removal

Hair removal is a significant part of transitioning for many transgender women (or females), particularly for those seeking a more stereotypical feminine appearance. The process helps alleviate dysphoria, boosts self-confidence, and enhances overall quality of life.¹⁹ The U,S, Food and Drug Administration recognizes laser hair removal as a permanent hair removal method.¹⁷ It targets melanin in hair follicles using laser light waves.¹⁹ An alternative, electrolysis, also removes hair permanently using a small probe inserted into individual hair follicles to administer an electric current.¹⁷

For individuals undergoing GAHT, healthcare providers need to keep specific considerations in mind. Among transgender women taking estrogen¹⁹

• Estrogen hormone therapy often results in an overall reduction in body hair, except for minimal effects on facial and genital hair.
• The extent of hair removal (complete hairlessness or retaining some hair) depends on personal preference and comfort levels.
• Many transgender women find facial and neck hair removal crucial for increased self-confidence, reduced dysphoria, and a sense of safety in public spaces.
• Those prioritizing gender-affirming lower surgeries like vaginoplasty (vagina construction surgery) require completely hair-free areas for surgery preparation, as hair growth within transformed tissue can cause complications.

For transgender men taking testosterone¹⁹

• Testosterone hormone therapy generally leads to increased body hair growth.
• Preparing for surgeries like phalloplasty (penis construction surgery) often requires completely hair-free skin areas for successful procedures, the specific area depending on the type of surgery planned.
• It is important to note that electrolysis doesn't prevent the growth of new hair follicles activated by testosterone. Therefore, new hair growth might occur in areas previously treated with electrolysis due to testosterone’s effects on stimulating hair follicles.

The adverse effects of hormone therapy may be beneficial for some patients, while being detrimental to others. It is critical for healthcare providers to educate patients on hair removal methods and their impact within the context of hormone therapy, so that patients understand what to expect.

Gender-Affirming Surgery

Gender-affirming surgery is often a crucial milestone for many, but not all transgender adults.³ Broadly classified into two categories, surgeries (1) directly impact fertility or (2) have no effect on fertility.³ Surgeries that alter fertility involve procedures like the removal of male genitalia (penis and gonads) for transgender women or the removal of female reproductive organs (uterus and ovaries) for transgender men.³ Surgeries that do not affect fertility include chest masculinization or breast augmentation, facial feminization, or facial masculinization surgeries.³

There is a lack of evidence supporting the routine discontinuation of hormone therapy before planned surgeries.²⁰ The majority of evidence advocating for estrogen cessation before surgery is derived from studies involving oral synthetic estrogen regimens (ethinyl estradiol), which are uncommon in transgender patients.¹⁹ WPATH advises maintaining estrogen therapy both before and after surgical procedures in transgender women, particularly in those without specific risk factors such as smoking, family history of VTE, or the use of synthetic estrogens.⁷ If the patient has the previously mentioned risk factors, the prescribing endocrinologist should discuss estrogen therapy cessation in the perioperative setting openly with the patient and make decisions collaboratively.²⁰ Typically, an acceptable timeframe for estrogen discontinuation is two to four weeks before the procedure.²⁰ Anticipated physiological and psychological withdrawal symptoms may include anxiety, autonomic hyperactivity, depression, decreased seizure threshold, and fatigue.²⁰ This comprehensive approach ensures a thoughtful consideration of hormonal factors in the surgical process for transgender women.

Evidence suggests that there is generally no need to discontinue testosterone treatment routinely in transgender men before scheduled or elective surgery despite the concern that testosterone can be aromatized to estradiol, which theoretically could increase the clotting risk.²⁰ A recent systematic review found no association of increased VTE complications after surgery with perioperative testosterone use.^21,22

The decision to undergo these surgeries is deeply personal and varies based on individual needs, preferences, financial access, and dysphoria. Access to comprehensive information, counseling, and support from healthcare professionals helps patients make informed decisions aligned with their gender identity and long-term goals while understanding the potential impact on fertility.³

PAUSE AND PONDER: A transgender patient would like to undergo breast augmentation but has only been on hormone therapy for six months. Is she eligible for the surgery?

Chest or “Top” Surgery

“Top” surgery is either removing breast tissue for a more masculine appearance or enhancing breast size and shape for a more feminine appearance. Breast surgery is a type of gender-affirming surgery with no impact on fertility.³ Since breast size varies among females, it is advisable for transgender women to postpone breast augmentation surgery until they have undergone at least two years of estrogen therapy.³ This is recommended because the breasts continue to grow during this period of hormone therapy.³

Meanwhile, the primary masculinizing surgery for transgender men is a mastectomy, which also has no impact on fertility.³ While breast size only partially regresses with androgen therapy, discussions about mastectomy in adults typically occur after androgen therapy starts.³ However, in some cases where trans-masculine adolescents present after significant breast development, a mastectomy may be considered approximately two years after starting androgen therapy and before the age of 18.³ Treatment decisions should be individualized based on the individual’s physical and mental health status. ³

Genital or “Bottom” Surgery

Genital or “bottom” surgery involves transforming and reconstructing the genitalia. According to The Endocrine Society Clinical Practice Guideline Criteria for Gender-Affirming Surgery, the following factors may influence decisions related to fertility preservation³:

1. Persistent and well-documented gender dysphoria
2. Meets the legal age requirement in the relevant country
3. Use of gender-affirming hormones for a continuous 12-month period, unless there is a medical contraindication
4. Successful in living full-time as a new gender role for the duration of 12 months
5. Well-controlled management of any significant medical or mental health conditions, if present
6. Demonstrated knowledge of practical aspects related to surgery, including cost, required lengths of hospitalizations, likely complications, and postsurgical rehabilitation.

Gender-affirming surgeries for transgender women that affect fertility include procedures like gonadectomy (orchiectomy), penectomy, and the creation of a neovagina.³ In the case of transgender men, surgeries that affect fertility include an oophorectomy, vaginectomy, complete hysterectomy, and the creation of a neopenis.³ Infertility can occur from both the temporary consequences of gender-affirming hormone therapy and permanent effects of gender-affirming surgeries (GAS).⁶ It is crucial to engage in ongoing discussions about infertility risks and fertility preservation options with transgender individuals and their families before and after initiation of therapies and surgeries.⁶

OTHER CARE IMPACTED BY GAHT

Anticoagulation

When assessing the risk of VTE associated with GAHT, it is crucial to consider the alternative—the risk of not providing GAHT.²² Withholding GAHT could lead to adverse mental health consequences that might outweigh the risk of VTE.²⁰ Some individuals may seek hormone therapy outside clinical care settings (that is, from unreliable sources) if healthcare providers refuse to provide it.²²

For transgender individuals experiencing VTE while on GAHT, treatment should align with current therapeutic anticoagulation recommendations for cisgender individuals.²⁰ The American Society of Hematology guidelines recommend direct oral anticoagulants (DOACs) over other options due to a lower risk of bleeding.²² Despite limited data in transgender people, recent case reports suggest DOACs are effective in those with VTE during GAHT. In severe cases threatening limbs, clinicians can consider thrombolysis and recommend it as they would in cisgender individuals.²² GAHT discontinuation during an acute VTE episode is often recommended, especially with above normal hormone levels, but this recommendation lacks extensive data.²² Clinicians and patients should discuss the potential risks and benefits of continuing GAHT during an episode.

Following acute VTE treatment, the decision to resume GAHT becomes complex. Many clinicians continue GAHT, even in patients with previous VTE, along with full-intensity anticoagulation to prevent recurrence.²² Although researchers have not conducted systematic evaluation in transgender patients, this approach was effective in cisgender women on hormone therapy.²² While cisgender patients may reduce anticoagulation dose after initial therapy, it is uncertain if dose reduction is prudent with GAHT. Shared decision-making, emphasizing the risks and benefits, remains crucial in determining the course of GAHT post-VTE treatment.

Estimating Kidney Function

Many healthcare providers are accustomed to using the Cockcroft-Gault equation to estimate kidney function.²³ This formula factors in sex, causing uncertainty as to how to calculate creatinine clearance in transgender patients. Although GAHT affects muscle mass and creatinine, using the duration of therapy is unreliable because the timing and magnitude of effect differ by individual. As such, cystatin C is often more accurate than creatinine. Acknowledging that cystatin C levels are not accessible at all practice sites, some experts suggest using the Cockcroft-Gault-calculated male and female creatinine clearance estimates as a range. Other methods include using vancomycin clearance calculations.²³

Fertility Preservation

Individuals who have transitioned may wish to have biological children for personal reasons, to maintain a genetic connection with their offspring, or to conform with cultural expectations.²² While many transgender individuals may not initially consider having children, their desires can change over time.²⁴ In a survey of 50 transgender men who had undergone gender-affirmation surgery, the majority (77%) had not contemplated fertility preservation before GAHT. An average of 9.9 years after starting testosterone therapy, 54% of participants wanted to have children.²⁵ The study also found that participants with children had a higher quality of life than those who did not have children.²⁵

Fertility preservation through the cryopreservation of sperm and oocytes is a well-established technique, available for pubertal, late pubertal, and adult individuals assigned male or female at birth^.6 Ideally, clinicians should present this option before initiating GAHT.⁷ Clinicians can offer embryo cryopreservation to adult transgender individuals, particularly those who have completed puberty, express a desire to have a child, and have a willing partner.⁷

While research has shown semen parameters may be compromised after the initiation of GAHT, a small study indicated that when treatment was discontinued, semen parameters were minimally altered.²⁶ In regards to oocyte preservation, there is no expectation that assisted reproductive technology (ART) treatments would be different for TGD patients compared to cisgender patients.⁷ The only potential variations are individuals with confounding factors related to infertility.⁷

Barriers to fertility preservation include financial constraints, invasiveness of procedures, and concerns about mistreatment or bias from healthcare providers.²⁴ Some fertility preservation procedures, such as sperm or egg collection, can serve as reminders of their sex assigned at birth and may trigger gender dysphoria.²⁴ Transgender individuals who pursued ART reported mixed experiences. Some have positive encounters with supportive providers who use gender-neutral language. Others experienced misgendering in clinical documentation.²⁴ Patients should be provided with options for future family planning whether they desire biological children or not.

BARRIERS IN PRACTICE

Laws and Legislation

When the Supreme Court tackled the Conservative challenge to the Affordable Care Act (ACA), the focus was on whether it was constitutional to mandate health insurance purchase.²⁷ This overshadowed Section 1557's anti-discrimination provisions protecting transgender individuals. The 2016 Rule, finalized by Health and Human Services, extended Title IX's anti-sex discrimination coverage to include "gender identity," ensuring equitable access to healthcare for transgender patients. The Trump administration attempted to reverse these protections but faced legal obstacles. This led to the Supreme Court's ruling in Bostock v. Clayton County, which affirmed protections for transgender individuals under existing civil rights statutes. Despite the Trump administration's efforts, subsequent legal challenges and judicial actions further emphasized protections for transgender individuals, leading to ongoing debates and policy shifts under the Biden administration.²⁷

The Bostock ruling, initially about employment, now impacts transgender minors' access to gender-affirming care.²⁷ Federal courts often interpret Title VII and Title IX together, meaning they see both statutes as prohibiting sex-based discrimination similarly.²⁵ This means that the Biden Administration can confidently enforce protections for gender identity under Title IX, following Bostock's reasoning.²⁷ Since Bostock's ruling was made under a majority conservative Supreme Court, it's unlikely to be reversed. This leaves opponents of gender-affirming care to explore other tactics, like raising religious objections or labeling such care as "experimental" or "medically dangerous."²⁷ These viewpoints circumvent many physicians’ clinical judgement, thus restricting how they practice medicine.

Over the past 18 months, the number of states implementing laws that restrict or prohibit minors' access to gender affirming care has increased dramatically.²⁸ Currently, the count of states with restrictions increased from just four states in June 2022 to 23 states by January 2024. Among these states, 17 have fully enacted their restrictions, while four face temporary injunctions, and one is permanently blocked pending appeal. The laws vary in complexity, with some focusing on specific aspects of gender affirming care, such as GAHT or gender affirming surgery. Additionally, while these laws primarily target minors' access to care, they often include provisions affecting other groups, such as parents, medical providers, and teachers.²⁸ These laws and policies cause potential harm to the wellbeing of young TGD, thus emphasizing the need for continued advocacy and support for inclusive and affirming practices.

Insurance Coverage

Ensuring comprehensive healthcare for transgender individuals requires access to both gender-affirming care and a wide range of inclusive services. However, numerous barriers have historically hindered access, with lack of health insurance coverage being shaped by intersecting factors at the individual, interpersonal, and structural levels.

Many state Medicaid programs exclude coverage for gender-affirming care, posing a significant concern given the elevated prevalence of poverty among transgender people. In a study utilizing Behavioral Risk Factor Surveillance System (BRFSS) data, gender non-conforming individuals were nearly twice as likely as cisgender women to report unmet care needs due to financial issues.²⁹According to the 2015 United States Transgender Survey, 25% of insured respondents encountered insurance discrimination.²⁹ Experiences included denial of coverage for gender-specific services, such as cancer screenings (13%), for care unrelated to gender affirmation (7%), and for gender-affirming surgery (55%) or hormone therapy (25%).²⁹ TGD individuals (33%) reported negative experiences related to being transgender when seeing a healthcare provider in the previous year, which includes verbal harassment, physical assault, or treatment refusal.²⁹ Additionally, 23% refrained from seeking care when needed in the previous year due to fear of mistreatment.²⁹

A 2019 systematic review revealed that 27% (range, 19% to 40%) of transgender individuals reported outright denial of healthcare.²³⁰ Assessments of provider readiness indicate that many clinicians lack training in transgender clinical and cultural competency, potentially contributing to interpersonal discrimination in healthcare settings.

Assessing Implicit Bias, Addressing Bad Behavior

1. Respect Gender Identity: TGD individuals deserve the same respect as cisgender patients. Address patients by their chosen name and pronouns, reflecting their gender identity. Avoid gossiping or making jokes about patients and treat them with the same respect you would want at work.³¹

2. Recognize Workplace Values: Understand the difference between your personal beliefs and the workplace values of dignity and respect for everyone. While you are entitled to your opinions, professionalism requires setting aside personal views and treating everyone with fairness and courtesy in the workplace.³¹

3.Seek Feedback and Learn from Mistakes: Don't be afraid to ask for feedback from TGD individuals about how you can better support them or avoid inadvertently causing harm. Be open to learning from your mistakes and apologize if you unintentionally offend someone. Additionally, take the initiative to stay updated on evolving terminology and practice recommendations, as ideas/norms about gender are fluid and change over time. Learning from reputable sources, such as The Trevor Project's Guide to Being an Ally to Transgender and Nonbinary Youth, shows a genuine commitment to fostering inclusivity and respect in the workplace.^31,32

4. Support Colleagues with Challenges: If you notice co-workers struggling to adjust to interactions with TGD individuals, offer gentle reminders about using the correct name and pronouns. Help them understand the impact of their behavior on both the TGD individual and the workplace environment. Encourage empathy and understanding to foster a more inclusive workplace culture.³¹

5. Intervene When Appropriate: If you witness blatant inappropriate behavior or discriminatory actions with no remorse towards a TGD individual in the workplace, don't remain silent. Find appropriate ways to intervene, whether it's addressing the behavior directly, reporting it to management, or offering support to the affected individual. Standing up against prejudice and discrimination helps create a safer and more inclusive work environment for everyone.³¹

CONCLUSION

Embracing gender diversity and providing gender-affirming care is essential in healthcare settings, including pharmacies. Pharmacists and pharmacy technicians who employ inclusive language and possess a thorough understanding of pharmacological interventions play a critical role for transgender individuals. Pharmacists can help tailor GAHT regimens to individual patient needs, promoting safety and helping patients achieve their goals towards gender affirmation. Pharmacists and pharmacy technicians can create a more inclusive and safer environment when interacting with patients. As healthcare workers in the pharmacy setting, we can provide patients with the resources they need without judgement.

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INTRODUCTION

Gene therapy is a medical approach to replace missing genes or correct dysfunctional genes in patients with genetic diseases. Gene therapies are best suited for patients who have well-defined, single (monogenic) mutations.^1,2 Many are rare diseases for which there are few, if any, treatment options. Therapeutics to correct gene mutations are biologics with the potential to cure a variety of previously incurable diseases such as muscular dystrophy, hemophilia, cystic fibrosis, and some types of blindness. Scientists are also developing gene therapies to stop cancer-causing genes and boost immune responses against tumors.

The term “gene therapy” encompasses multiple broad strategies that can be separated into two general approaches: in vivo (performed inside an organism) and ex vivo (cells that are removed from the organism, genetically modified, and then returned to organism).³ Within these approaches, multiple techniques and delivery systems are currently used or in development:^4,5

• Viral vectors (in vivo or ex vivo)
• Non-viral delivery particles (in vivo or ex vivo)
• Gene editing (in vivo or ex vivo)
• Cell engineering (ex vivo only)

The entire field of gene therapy is beyond the scope of this activity. This activity’s focus will be in vivo gene delivery via engineered adeno-associated virus (AAV), with some discussion of gene therapy’s basics and background. This is valuable information for pharmacists and pharmacy technicians as this complex biologic class matures and more gene therapies become available to patients.

BASICS OF GENE THERAPY

Gene Therapy Terminology

People outside of the field may be unfamiliar with many terms used to describe gene therapies. Table 1 defines common terms.

Table 1. Common Terms Used to Describe Gene Therapy^6,7,8

DNA, deoxyribonucleic acid.

We have used brand drug names preferentially throughout this activity because generic names for gene therapies are complex (See Sidebar).

SIDEBAR: What’s in a Name? How Are Gene Therapies Named?^9,10

For in vivo gene therapies, the generic names are composed of two words:

• First word corresponds to the gene component
  • Prefix: random element to provide unique identification
  • Infix: element to denote the gene’s pharmacologic class (gene’s mechanism of action)
  • Suffix: element to indicate “gene”
• Second word corresponds to the vector component
  • Prefix: random element to provide unique identification
  • Infix: element to denote the viral vector family
  • Suffix: element to identify the vector type (non-replicating, replicating, plasmid)
  • 4-letter distinguishing suffix: devoid of meaning and attached to the core name with a hyphen

Example:

The Pros and Cons of Gene Therapy 

Patients and/or caregivers considering gene therapy should consider several factors^11-13:

• Duration of efficacy
  • PRO: Potential exists for permanent correction of a disease state. If successful, patients may not need lifelong treatments/medications.
  • CON: Gene therapy is relatively new and long-term efficacy data is lacking. If gene expression wanes over time, patients may need redosing (which may be impossible) or alternative treatments.
• Safety
  • PRO: Regulatory agencies have approved several products, and safety data is available.
  • CON: Complete understanding of adverse effect mechanisms is lacking, and long-term safety information doesn’t exist.
• Cost
  • PRO: A curative gene therapy may be more cost-effective than a lifetime of other medications/treatments.
  • CON: Available gene therapies are very expensive, $2.9 to $3.5 million for the AAV in vivo therapies approved in 2022 and 2023.

The History of Gene Therapy

Gene therapy is a relatively new field. Clinicians ran the first clinical trial in 1990. Scientists made several advancements in the 1990s and early 2000s, and progress has rapidly accelerated since then.¹⁴ (See Sidebar).

ABBREVIATIONS: AAV, adeno-associated virus vector; Ad, adenovirus; ADD, adenosine deaminase deficient; ALL, acute lymphoblastic leukemia; CALD, cerebral adrenoleukodystrophy; CAR T, chimeric antigen receptor; Cas9, CRISPR-associated protein 9; CRISPR, clustered regularly interspaced palindromic repeats; DMD, Duchenne muscular dystrophy; EMA, European Medicines Agency; FDA, Food and Drug Administration; HSC, human stem cells; LV, lentivirus; DLBCL, diffuse large B-cell lymphoma; SCD, sickle cell disease; SCID, severe combined immunodeficiency disorder; SMA, spinal muscular atrophy; TDT, transfusion-dependent thalassemia.

Gene Therapy Systems

Viral Vectors

Prototypical gene therapy is an in vivo approach to curing genetic diseases. It uses a delivery vehicle, such as an engineered virus that encapsulates the gene of interest (GOI) for injection into a patient by various routes, such as intravenous (IV), intraocular, or intrathecal.³⁹ This method takes advantage of a virus’s natural ability to enter mammalian cells efficiently. Once the delivery vehicle enters host cells, the encapsulated gene drives production of the missing or faulty protein. Clinicians use this approach for diseases such as muscular dystrophies, where mutations in the dystrophin gene cause progressive weakness and muscle-wasting, and cystic fibrosis, where mutations in the cystic fibrosis transmembrane conductance regulator gene impair lung function.

Non-viral Delivery Vehicles

Non-viral delivery vehicles, such as nanoparticles, can also deliver genes or gene editing systems in vivo. These particles use biocompatible materials such as polymers and lipids to carry genes or nucleic acids into cells.³ Researchers can customize a particle’s physiochemical properties to target the intended cell types better and evade immune responses. Non-viral particles are less efficient than viruses at entering cells but may have several other advantages. It’s likely that most patients are immunologically naïve to manufactured particles and lack pre-existing antibodies that may prevent successful uptake by cells. Non-viral particles may also be easier to manufacture and purify, making them more cost-effective to produce than viral vectors.⁴⁰

Recent gene therapy clinical trials using nanoparticles or lipid nanoparticles include the following^41-43:

• Reqorsa: contains a tumor suppressor gene encapsulated in a lipid nanoparticle for treatment of several types of lung cancer
• NTLA-2001: contains a gene editing system encapsulated in a lipid nanoparticle for treatment of hereditary transthyretin amyloidosis (a disease which deposits abnormal protein [amyloid] in organs)

Gene Editing Systems

Gene editing systems, which can be in vivo or ex vivo approaches, can provide precise, targeted gene modifications. Gene editors are engineered nucleases (enzymes) that produce double-stranded breaks at a specific target site. These breaks stimulate the cell’s natural DNA repair mechanisms, resulting in the repair of the break by homology-directed repair or non-homologous end joining. With these systems, target-specific DNA insertions, deletions, modifications, or replacements are all possible.^3,44

Many gene editing tools exist, including^3,44

• clustered regularly interspaced short palindromic repeats (CRISPR) Cas-associated nucleases
• transcription activator-like effector nucleases (TALENs)
• zinc-finger nucleases (ZFNs)
• meganucleases (MNs)

Gene editing ex vivo systems are a fast-growing area with many programs in development.⁴¹ In vivo gene editing is rife with challenges, especially those concerning delivery to the intended cells. Gene editing systems are an evolving cutting-edge platform reviewed in much more detail elsewhere.^3,44,45

Ex Vivo Gene Therapy

In ex vivo gene therapy, medical and/or laboratory personnel remove a patient’s cells from the body, genetically modify them (using viral vectors, non-viral delivery particles, or gene editing systems), and then re-introduce them into the patient. Alternatives to the use of a patient’s cells include genetically modified cell lines or cells from another donor. The use of autologous (patients’ own) cells avoids the need to find an immuno-compatible donor. Examples of systems include chimeric antigen receptor (CAR) T cells and engineered hematopoietic stem cells (HSC). CAR T cells are T lymphocytes that are modified to recognize tumor antigens, such as the B lymphocyte antigen Cluster of Differentiation-19 (CD-19) and B-cell maturation antigen (BCMA). Once genetically modified, the CAR T cells bind to cells expressing the tumor antigen and subsequently kill them. HSC have the ability for self-renewal and to differentiate into multiple cell lineages, therefore engineering them to correct genetic flaws such as enzyme deficiencies and hemoglobinopathies (inherited disorders affecting hemoglobin, the molecule that transports oxygen in the blood) makes them a promising approach.

Several products have received regulatory approval in the United States (U.S.)⁴⁶:

• Autologous CAR T cells^47-50
  • CD19-directed autologous T cell immunotherapies for the treatment of various types of B cell lymphomas include the following:
    • Yescarta (axicabtagene ciloleucel) – approved 2017
    • Kymriah (tisagenlecleucel) – approved 2017
    • Tecartus (brexucabtagene autoleucel) – approved 2020
    • Breyanzi (lisocabtagene maraleucel) – approved 2021
  • BCMA-directed autologous T cell immunotherapies for treatment of relapsed or refractory multiple myeloma include the following^51,52:
    • Abecma (idecabtagene vicleucel) – approved 2021
    • Carvykti (ciltacabtagene autoleucel) – approved 2022
• Autologous HSC-based gene therapies include the following^53-56:
  • Skysona (elivaldogene autotemcel) – slows neurological dysfunction in cerebral adrenoleukodystrophy by inducing synthesis of adrenoleukodystrophy protein – approved 2022
  • Zynteglo (betibeglogene autotemcel) – corrects β-thalassemia by adding functional copies of a modified β-globin gene into the patient’s HSC – approved 2022
  • Casgevy (exagamglogene autotemcel) – first FDA-approved CRISPR/Cas9 gene-editing therapeutic; corrects sickle cell disease (SCD) and transfusion-dependent β-thalassemia by adding functional copies of a modified β-globin gene into the patient’s HSC – approved 2023
  • Lyfgenia (lovotibeglogene autotemcel) – corrects SCD by adding functional copies of a modified β-globin gene into the patient’s HSC – approved 2023

CAR T cell gene therapy is an effective treatment for several types of cancers but comes with many challenges to patients, medical professionals, and pharmacy personnel. Product manufacturing, administration, and adverse effect mitigation are more complex than for many other treatment types. Medical, laboratory, and/or pharmacy personal carry out the following key steps at specialized medical centers^47-50:

1. Collect the patient’s white blood cells (leukapheresis)
2. Manufacture the CAR T cells in a laboratory with a typical time frame of two to four weeks
   • Patients may need to travel to and remain near the center while they wait for the cells
   • If the process fails, then personnel must repeat the cell collection and CAR T cell manufacturing
3. Administer chemotherapy to deplete the patient’s lymphocytes, two to 14 days prior to CAR T cell infusion, which makes room for the CAR T cells
4. Administer the CAR T cells to the patient by slow infusion to minimize infusion-related adverse reactions
5. Monitor the patient for at least four weeks, likely requiring the patient to stay at or near the treatment center

This therapy class carries Boxed Warnings:

• CD-19 directed therapies^47-50,57
  • Cytokine release syndrome (CRS): over-activation of the immune system with release of large amounts of cytokines (immune system proteins); this is a common, potentially life-threatening adverse event
  • Neurotoxicity: the mechanism by which this occurs is not well understood, but it is common and can be life-threatening

• BCMA-directed therapies^53,54
  • CRS and neurotoxicity as listed for CD-19 directed therapies
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a hyperinflammatory immune response that can be life-threatening
  • Prolonged cytopenia (low numbers of blood cells) with bleeding and infection; can be life-threatening

Ex vivo gene therapy with autologous HSC is also a complex process with multiple challenges and toxicities.^53,54 For these therapies, medical personnel pretreat patients with granulocyte-colony stimulating factor to increase production and release of HSCs from bone marrow. Laboratory staff then collect and purify HSC from the patient’s blood. Staff may need to collect cells more than once to amass the required number of cells or in cases where manufacturing fails. Laboratory staff genetically modify the patient’s HSCs, typically with a lentiviral vector, to express the GOI. The cell manufacturing process can take up to three months. The modified cells require cryopreservation and liquid nitrogen storage conditions, adding to the process’s complexity.

When the cells are ready, medical personnel administer lymphocyte-depleting chemotherapy to the patient to remove HSCs that are making the faulty protein and to make room in the bone marrow for the genetically modified HSCs. Next, medical personnel infuse the thawed HSCs to the patient intravenously. After infusion, patients may need to stay at the medical center for several months for recovery and monitoring.

The prescribing information lists toxicities including prolonged cytopenias, serious infections, and an increased risk for lentiviral vector-mediated oncogenesis (development of a new cancer). It recommends patient monitoring for 15 years to life for hematologic malignancies. Skysona and Lyfgenia have Boxed Warnings for hematologic malignancy.^53,56

The overview above describes how the field of gene therapy is broad and encompasses multiple approaches. New and evolving approaches include non-viral delivery, gene editing, and ex vivo cell engineering; they have recently started to become available to patients. This is an exciting and hopeful time for patients with genetically-linked diseases, and it is likely that many more effective and approved therapies will be available soon.

AAV-BASED IN VIVO GENE THERAPY

Although researchers are developing viral vectors based on many types of viruses (e.g., adenovirus, gamma retrovirus, herpes simplex virus, lentivirus) adeno-associated virus (AAV) has emerged as the leading viral vector for in vivo gene therapy with five current regulatory approvals in the U.S. and many more programs under development.^41,46 Its favorable characteristics include not causing human disease, inability to replicate in the host without a helper virus, and ability to elicit a low host immune response relative to many other viruses. Since the expression cassette is typically maintained on an episome, scientists expect AAV-based vectors to have a low frequency of integration into the host genome, conferring a minimal risk of cancer.⁵⁸ In addition, at least one serotype of AAV (AAV9) can cross the blood-brain barrier making AAV a suitable choice for neurologic diseases without invasive local administration of the vectors into the brain. Researchers find AAV-based vectors to be attractive, versatile tools with suitable properties and utility for a wide variety of diseases.

AAV Biology

Naturally occurring AAVs are small, non-enveloped viruses that belong to the Parvovirus family. They have a linear single-stranded DNA genome of approximately 4.7 kilobases, including rep and cap genes that encode for replication and capsid proteins, respectively.³ Figure 1A illustrates the genomic structure of a wild type (naturally occurring) AAV.

In engineered AAVs used for gene therapy, developers remove the rep and cap genes and replace them with an expression cassette, as illustrated in Figure 1B. The expression cassette contains the GOI, regulatory elements (promoter/enhancer), and poly-adenosine tail (to stabilize the messenger RNA and facilitate translation into protein) flanked by inverted terminal repeats (ITRs; required for genome replication and packaging). The expression cassette replaces approximately 96% of the native genome.³

Figure 1. Genomic Structure of Wild Type AAV and Engineered AAV Vector

cap, capsid gene; GOI, gene of interest; ITR, inverted terminal repeat; rep, replicase gene.

AAV capsids in both the wild type AAV and engineered AAV vectors are composed of three viral proteins (VPs) named VP1, VP2, and VP3. Sixty molecules of these proteins, estimated to exist in a 1:1:10 ratio (VP1:VP2:VP3), assemble into each icosahedral capsid (Figure 2). The VP sequences overlap, with VP1 being 137 amino acids longer than VP2, which is 57 amino acids longer than VP3. Differences in VP3 sequences distinguish one AAV serotype from another.⁵⁹

Figure 2. Protein Structure of the AAV Capsid

VP, viral protein.

AAV exists as at least 11 natural serotypes, which share about 51% to 99% sequence identity in their VP3 protein.^60,61 Sequence comparisons between different AAV serotypes identified nine variable regions situated on the capsid surface. The specific amino acid sequences of these regions impact AAV binding to host cell receptors, thus determining cell- and tissue-specific tropism (affinity for a specific tissue or cell type). These variable sequences also function as binding sites (epitopes) for AAV-specific antibodies, thus influencing host immune responses.⁶²

An AAV serotype can be tropic to multiple cell types and tissues, and multiple serotypes can be tropic to the same cells/tissues. Researchers isolate serotypes from non-human primates and develop synthetic serotypes using protein engineering to alter tropisms and/or evade pre-existing AAV-specific antibodies.¹

PAUSE AND PONDER: If your child had a life-shortening genetic disorder and a new AAV9-based therapy became available, how would you feel if your child had a high anti-AAV9 neutralizing antibody titer that excluded them from clinical trials or treatment?

Neutralizing antibodies (NAbs) are naturally occurring antibodies that bind to AAV surface epitopes and block uptake into target cells. NAb binding to the AAV capsid can induce rapid clearance of the gene therapy by the patient’s immune system. Clinical personnel must screen patients for pre-existing Nabs. Trial protocols and prescribing instructions often exclude patients with NAbs specific for the gene therapy’s serotype.

Older children and adults tend to have a high prevalence of pre-existing antibodies against commonly circulating (wild type) AAV serotypes because of previous exposure to these viruses over the course of their lives. For example, studies showed that approximately 40% of humans have NAbs to AAV serotypes 5, 6, 7, 8, and 9.⁶³ Between 6% and 95% of individuals with hemophilia A and B have AAV-specific antibodies based on AAV serotype and assay used.⁶⁴ In addition, due to the high degree of conservation of capsid protein amino acid sequences, pre-existing antibodies to one serotype may cross-react with other serotypes, further limiting the availability of a therapy for a patient. Patients without NAbs prior to gene therapy will develop high titers of NAbs following vector administration, rendering them ineligible for additional rounds of gene therapy with the same vector or a cross-reactive serotype.^1,63-65

Vector Design

To create a vector for a particular disease, drug developers try to target an AAV vector to the specific cell or tissue type where gene correction is needed. The capsid serotype choice significantly influences this decision.

AAV2, AAV5, AAV6, AAV8, and AAV9 account for a majority of the ongoing AAV gene therapy clinical trials.^60,66 Commonly, AAV2 or AAV8 is the choice for ocular therapies; AAV2, AAV8, AAV5, and AAV9 are best for liver targeting; and AAV2 and AAV9 are preferred targeting muscle or the central nervous system. Some researchers are also using AAV serotypes isolated from rhesus monkeys, such as rh74.^60,67 As discussed, AAV9 can cross the blood-brain barrier, allowing IV administration of this serotype to target brain tissue while avoiding invasive intrathecal injections.^60,68 Therefore, AAV9 is a popular vector to treat many diseases affecting the nervous system.

Developers derive the capsids of AAV vectors either from natural AAV viruses or by engineering capsids through rational design, directed evolution, or computer-guided strategies. The impetus to develop AAV vectors with capsids from less common AAV serotypes or novel engineered AAV capsids serves to improve or modify tissue targeting and circumvent immune recognition.⁶⁹

Considerations for vector design include^61,62

• Choosing the best AAV serotype to target the intended cell type or tissue, using the desired route of administration
• Potential for tissue-specific promoters (e.g., targeting the muscle for muscular dystrophy or the liver for hemophilia) rather than constitutive promoters (that will drive gene expression in a wide range of tissues and perhaps result in off-target toxicity)
• Whether an enhancer is needed to boost expression in the target tissue to achieve desired therapeutic effect
• Modifying capsid epitopes to reduce recognition/response from the host immune system

Vector Production and Purification

Once developers choose the best capsid serotype and design the vector, they proceed to the manufacturing step. Gene therapies are complex biologics, and manufacturing and purification are of utmost importance for efficacy, safety, and product stability. Regulatory agencies require good manufacturing practice compliance.⁷⁰

Scientists commonly use mammalian cell lines to propagate engineered AAV vectors and then purify the vectors from cell lysates. Rigorous purification is essential. As the science of gene therapy matures, drug developers continuously improve purification methods. Contaminants from the engineered AAV cultivation process are a potential source of toxicity and can induce unwanted immune responses. Release testing of the final product in the U.S. must comply with a series of FDA-established requirements and predetermined specifications to determine product safety, purity, concentration, identity, potency, and stability.⁷¹ Characterization of the final product includes a determination of the viral genome (vg) titer, infectious titer (potency), product identity (AAV capsid and genome), and therapeutic gene identity (expression/activity).⁷²

Gene therapy developers follow these steps to manufacture AAV-based therapies^73-75:

1. Use conventional recombinant DNA technology in bacterial systems to produce the plasmids
2. Use mammalian cell lines, such as human embryonic kidney 293 cells, or insect cell lines, such as the baculovirus/insect cell system, to produce the vectors
3. Transfect (introduce genetic material into a cell) three plasmids into the cell line
   • a recombinant AAV plasmid containing the expression cassette (see Figure 1b)
   • an adenovirus-based helper plasmid supplying genes needed for virus replication
   • a plasmid containing the essential rep and cap genes needed for virus replication and capsid formation
4. Collect produced vectors from the cells and purify them. Complex purification processes require multiple methods that may be specific for each individual contaminant. Rigorous purification minimizes patient risk (see Sidebar). Examples of purification process steps (and techniques used) include the following:
   • Cells lysis to release the viral particles (detergent, mechanical stress, hypertonic shock, freeze-thawing)
   • Removal of nucleic acids (nuclease treatment), cell fragments and proteins, cell culture contaminants (centrifugation, filtration, chromatography)
   • Separation of full vector particles from empty particles (cesium chloride gradient ultracentrifugation or chromatography)
5. Formulate vectors after purification for administration to the patient. Formulation optimization prior to manufacture is not trivial. Some considerations are:^73-75
   • Formulation chemical composition must be optimized for intended route of administration
   • Formulation must be sterile and have low endotoxin concentration
   • Formulation must minimize product degradation to avoid aggregation and loss of efficacy due to product instability

SIDEBAR: Patient Safety: The Importance of Purification of AAV^69,74

• Non-vector sequences (including plasmid DNA, helper virus DNA, and DNA from the cell line used to produce the vector) can unintentionally be packaged into the capsids. AAV vector genomes can recombine with non-vector DNA, resulting in AAV vectors that contain chimeric (mixtures of DNA from different sources) sequences. The behavior of these unintended sequences is unpredictable in patients.
• Capsids containing the complete intended therapeutic gene, partial sequences, unintended chimeric sequences, or no genetic sequence material at all (empty capsids) are all possible outcomes of vector manufacturing. Administering a mixture of different forms of the therapeutic to patients may result in a partial effective dose, thus lowering potency and necessitating administration of higher overall numbers of AAV particles to achieve efficacy. The higher the number of AAV particles, the higher the risk of toxicities and immune system activation.

Toxicities/Adverse Events

Although AAV gene therapy is generally considered safe, multiple treatment-emergent serious adverse events have occurred following gene therapy administration to patients. These include severe hepatoxicity and thrombotic microangiopathy (TMA). Other potential toxicities and identified risks include myocarditis, neurotoxicity (dorsal root ganglion [DRG] degeneration), oncogenicity, and immunotoxicity.⁶⁹

In general, AAV vectors administered IV first travel to the liver. Liver enzyme increases denoting liver damage commonly occur and corticosteroid treatment is often effective. On occasion, acute serious liver injury, liver failure, and death have occurred. Although the mechanism is not completely understood, more severe liver injury appears to correlate with higher vector doses. Severe liver injury following AAV vector administration for spinal muscular atrophy (SMA) and X-linked myotubular myopathy genetic diseases has occurred.^69,76

TMA is a pathological condition characterized by formation of thrombi (clots) in small blood vessels, following endothelial cell injury. TMA’s clinical presentation often includes complement activation, cytokine release, thrombocytopenia (decreased platelets), and kidney injury/failure. Several cases of TMA have been reported in patients or clinical trial participants following AAV gene therapy for SMA and Duchenne muscular dystrophy (DMD). Treatments for affected patients included hemodialysis, platelet transfusion, and the complement inhibitor eculizumab. As with severe liver injury, TMA development appears to be related to high vector doses.^77,78

Several patients in DMD clinical trials have developed myocarditis, which was fatal in one patient. A hypothesis is that pre-existing inflammation in DMD patients’ muscles, including heart muscle, worsened upon local expression of dystrophin. Steroid treatment successfully resolved myocarditis in some cases.⁷⁹

DRG degeneration/toxicity is an identified potential risk of AAV gene therapy. DRGs are collections of sensory neurons that relay impulses from the periphery to the central nervous system. Researchers have observed AAV vector-induced DRG toxicity mainly in non-clinical studies with pigs and non-human primates. Direct administration of AAV into cerebral spinal fluid and high vector doses were contributing factors. Pathology studies have detected DRG degeneration in autopsy samples from humans who received AAV gene therapy. Scientists do not completely understand DRG toxicity’s underlying mechanisms in animals or the significance of clinical translation to humans.⁸⁰

Oncogenicity due to insertional mutagenesis (introducing foreign DNA into a person’s genome) is a potential risk of gene therapy. Studies in mice that received AAV vectors revealed integration events and hepatocellular carcinoma. Hepatocyte clonal expansion occurred in dogs following AAV vector administration although tumors were not found. AAV vector genome integration into chromosomes has been detected in humans, but so far AAV-associated oncogenesis has not been reported.⁵⁸ Due to the potential risk, regulators expect long-term monitoring after vector administration.^69,81

Although immune responses to wild type AAV are low relative to other viruses, AAV can engage all arms of the immune system and can do so robustly especially when high vector doses are administered. The immune response to AAV gene therapy is complex, and poorly understood, and can contribute to loss of efficacy and adverse effects. Local (rather than systemic) dosing, use of tissue specific promoters, and increasing the vector’s potency (increasing promoter strength/achieving higher levels of expression per AAV particle) may effectively minimize toxicity.^65,76,82,83

Immune responses to AAV gene therapy include the following^65,66,79,82:

• Innate immune responses: may lead to cytokine induction and/or activation of the complement cascade (e.g., toll-like receptor recognition and signaling in response to capsid proteins and nucleic acids)
• Humoral responses: antibody binding to AAV capsid may activate complement and immune cells and remove the vector from circulation before it can reach its target tissue. After gene therapy administration, the body generates new antibodies that can be specific for a capsid or transgene product.
• Cellular immune responses: may lead to inflammation and elimination of the cells producing the disease-correcting protein (e.g., activation/expansion of capsid- or transgene-product-specific cytotoxic T lymphocytes)

APPROVED IN VIVO GENE THERAPIES

As of December, 2023, the FDA approved eight in vivo gene therapies, five of which are AAV based.⁴⁶

Non-AAV-Based Therapies

Three of the FDA-approved in vivo gene therapies are non-AAV based; they are adenovirus (Ad)-based or herpes simplex virus (HSV)-based. None are systemically administered, but instead are administered locally to the skin or bladder.

Vyjuvek (beremagene geperpavec-svdt) is a live, replication deficient HSV type 1 (HSV-1) vector genetically modified to express human type VII collagen. Vyjuvek is indicated for wound treatment in patients with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain gene. Topical application to wounds induces production of the mature form of type VII collagen leading to wound healing.⁸⁴

Adstiladrin (nadofaragene firadenovec-vncg) is a non-replicating adenoviral serotype 5 vector genetically modified to produce human interferon α-2b (IFNα-2b). Adstiladrin is indicated for patients with high-risk Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. Intravesical (within the bladder) instillation results in local expression of IFNα-2b protein that is anticipated to have anti-tumor effects.⁸⁵

Imlygic (talimogene laherparepvec) is a live, attenuated HSV vector genetically modified to replicate within tumors and to produce the immune stimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). Imylgic is indicated for local treatment, by intralesional injection of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Imylgic causes tumor lysis followed by release of tumor-derived antigens, which together with virally derived GM-CSF may promote an antitumor immune response. However, the exact mechanism of action is unknown.⁸⁶

AAV-Based Therapies

Luxturna (voretigene neparvovec-rzyl) is a genetically modified non-replicating AAV2 expressing the human retinoid isomerohydrolase (RPE65) gene approved in 2017. It’s used to treat patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy, a condition causing progressive retinal degeneration and dysfunction, which can lead to vision loss and blindness over time. Retinal pigment epithelial (RPE) cells produce RPE65. Mutations in this gene result in vision impairment, so Luxturna aims to correct these mutations. A clinician administers 1.5 x 10¹¹ vg of Luxturna subretinally (directly into the space beneath the retina) to each eye on separate days, at least six days apart. Patients typically take systemic oral corticosteroids starting three days before its administration and continuing with a tapering dose for 10 days. Preparation of Luxturna for administration is complex and includes thawing, dilution, and preparation of syringes for injection. Warnings and precautions include endophthalmitis (infection/inflammation of the inner structures of the eye), permanent decline in visual acuity, retinal abnormalities, increased ocular pressure, intraocular air bubble expansion, and cataracts. Immune responses to Luxturna were mild in clinical trials, perhaps due to corticosteroid administration.²³

Zolgensma (onasemnogene abeparvovec-xioi) is a genetically modified non-replicating AAV9 expressing the human survival motor neuron (SMN) protein. The FDA approved it in 2019 for treatment of patients younger than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the SMN1 gene. SMN protein is key for muscle development and movement and Zolgensma aims to correct these mutations to treat the disease. After Zolgensma is thawed, a clinician administers 1.1 × 10¹⁴ vg/kg of Zolgensma intravenously by slow infusion. Patients typically take systemic corticosteroids starting one day before Zolgensma administration and continuing for a total of 30 days. Serious adverse effects described in the Boxed Warning include acute liver injury and failure with fatal outcomes. Other warnings and precautions include systemic immune response, thrombocytopenia, TMA, and elevated troponin (a protein involved in muscle contraction).⁸⁷

Hemgenix (etranacogene dezaparvovec-drlb) is a genetically modified non-replicating AAV5 expressing human coagulation Factor IX (Padua variant), under control of a liver-specific promoter. Approved in 2022, it is employed to treat male patients with hemophilia B (congenital Factor IX deficiency). The Padua variant has an 8-fold higher specific activity relative to wild type Factor IX, and Hemgenix would ideally correct the disease by providing circulating Factor IX activity. Clinicians administer 2.0 × 10¹³ gc/kg of Hemgenix by slow intravenous infusion. Hemgenix is a refrigerated suspension that requires dilution into normal saline. The prescribing information recommends corticosteroids, not prophylactically, but only if the liver enzyme aspartate aminotransferase (AST) increases to twice the patient’s baseline value. Warnings and precautions include infusion reactions (including anaphylaxis), hepatotoxicity, and hepatocellular carcinogenicity (theoretical risk if vector DNA integrates into the host cell genome).⁸⁸

Elevidys (delandistrogene moxeparvovec-rokl) is a genetically modified non-replicating AAVrh74 (originally isolated from rhesus monkeys) expressing human micro-dystrophin. The FDA approved it in 2023 for treatment of ambulatory 4- to 5-year-old patients with DMD with a confirmed mutation in the dystrophin gene. The vector’s promoter/enhancer drives transgene expression predominantly in skeletal and cardiac muscle. The dystrophin protein’s micro version consists of selected domains of dystrophin that confer function to muscle cells. After Elevidys is thawed, clinicians administer 1.33 × 10¹⁴ vg/kg by intravenous infusion using a syringe infusion pump. The prescribing information recommends prophylactic corticosteroids following a complex administration and tapering schedule, which is further complicated in patients with DMD already on a corticosteroid regimen. Warnings and precautions include acute serious liver injury, immune-mediated myositis, and myocarditis.⁸⁹

Roctavian (valoctocogene roxaparvovec-rvox) is a genetically modified non-replicating AAV5 expressing the B-domain-deleted form of human coagulation Factor VIII (the smallest active form of Factor VIII) under control of a liver-specific promoter. Approved in 2023 for treatment of male patients with severe hemophilia A, clinicians administer Roctavian after thawing at 6.0 × 10¹³ vg/kg by intravenous infusion using a syringe infusion pump. The prescribing information recommends corticosteroids, not prophylactically, but only if liver enzymes increase to 1.5 times the patient’s baseline or to above the upper limit of normal. Warnings and precautions include infusion reactions (including anaphylaxis), hepatotoxicity, and thromboembolic events.⁹⁰

PAUSE AND PONDER: The prescribing information for Hemgenix and Roctavian do not recommend these gene therapies for women. Why?

A LOOK TO THE FUTURE

As discussed above, the FDA has approved five AAV-based gene therapies, Figure 3 illustrates disease indications being studied in AAV-based clinical trials including 90 ongoing, interventional studies.⁴¹

Figure 3. AAV-based gene therapy clinical trials for different disease indications as a percentage of all AAV-based clinical trials for therapies not yet approved for marketing⁴¹

The percentages of each disease indication were calculated based on the total of current AAV-based interventional clinical trials. Clinical trials were identified using the search terms gene therapy and adeno-associated (for condition/disease) and interventional (study type). Trials designated as recruiting, active – not yet recruiting, enrolling by invitation, and completed were included in the analysis (n = 73). Trials designated as terminated, suspended, or unknown status were not included. Data are current as of April 12, 2024.

Ophthalmology and neurology represent the highest percentage of forthcoming therapies. Within the ophthalmology category, multiple trials are underway for achromatopsia (color blindness), amaurosis (complete vision loss without visible eye damage; typically, an optic nerve disease), and retinitis pigmentosa (progressive vision loss due to retina deterioration), among others. The neurological disease category includes trials for Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and others. Hematological and musculoskeletal clinical trials are highly focused on hemophilia and muscular dystrophies, respectively. The metabolic disease category is diverse containing a few trials each for numerous genetic diseases.⁴¹

Controlling the immune response to AAV vectors is one of the biggest hurdles for future therapeutics. The human immune system is complex and very efficient. Often, it has a back-up plan in case an organism escapes the first round of attack and usually a back-up plan for the back-up plan. It becomes impossible for an AAV vector (a virus in sheep’s clothing) to go unnoticed, especially when the doses are greater than 1 trillion vg/kg of body weight. Thus, a patient’s immune system will go into action starting shortly after receiving gene therapy and mount a multi-pronged attack.

New and improved strategies to control immune responses will greatly benefit patients. Researchers are diligently pursuing strategies (Table 2) that target the vector itself or immune system components.^91-93 Success will probably use a combinations of strategies.

Table 2. Strategies to Control or Circumvent Immune Responses^91-94

AAV, adeno-associated virus; IdeS, immunoglobulin G-degrading enzymes of Streptococcus pyogenes; IgG, immunoglobulin type G; NAb, neutralizing antibody.

Perfection of technologies to remove pre-existing NAbs would allow many more patients to be eligible for gene therapies. Curbing antibody production in the days following the gene therapy may boost efficacy, reduce toxicity, and allow patients to remain eligible for more than one round of AAV gene therapy if needed. Methods to control T cell-mediated responses would prevent destruction of the cells producing the transgene product, increasing the persistence of the curative gene expression.

Early clinical studies took a reactive approach to immune responses to AAV; they used medications such as corticosteroids following observation of increases in liver enzymes or signs of inflammation. More recently, efforts to identify drugs and combinations of drugs that will suppress the immune response prophylactically have accelerated^91,93:

• Corticosteroids (e.g., methylprednisolone): general anti-inflammatory
• Tacrolimus: inhibits T cell proliferation and differentiation
• Rituximab: depletes B cells to block antibody production
• Rapamycin (sirolimus): disrupts cytokine signaling resulting in inhibition of B cell and T cell activation
• Mycophenolate mofetil: inhibits B cell and T cell proliferation
• Eculizumab: complement inhibitor
• Hydroxychloroquine: inhibits toll-like receptor-9-mediated responses to viral DNA an antigen presentation

Researchers must investigate other key variables: the timing of immunosuppression initiation and the requisite treatment duration.

Many clinical trials have employed corticosteroids, but corticosteroids alone are insufficient to control immune responses. Regulators have approved the immunosuppressants listed above for indications other than gene therapy, and their safety profiles are known, making them logical choices to investigate for gene therapy indications. Future work must maximize safety and efficacy of AAV gene therapy while balancing adverse effects of the immunosuppressive regimens.⁹³

SUMMARY

Gene therapy is a relatively new, complex, and evolving field in medicine that offers hope to patients with previously incurable genetic diseases. The information presented here is intended to introduce a topic that pharmacists and pharmacy technicians may not have been previously exposed to, and perhaps inspire them to read more.

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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 0009-9999-24-023-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.

• Drs. Micelli and Coughlin do not have any relationships with ineligible companies.

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).¹ Autism 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

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

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.¹⁰ Pharmacists 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.⁸ However, 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.¹⁷ In 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.”

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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:

1. A fasting plasma glucose level of 126 mg/dL (7 mmol/L) or higher
2. A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-gram oral glucose tolerance test
3. 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
4. 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:

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

2. 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

3. 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.¹⁶ According 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%.¹⁶ Dietary 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.²¹ In 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.²⁷ Higher medication adherence, as would be expected, is associated with improved glycemic control, fewer emergency department visits, decreased hospitalizations, and lower medical costs.²⁸ Patients 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.³⁰ Renal 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.⁵ Diabetes 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.³³ The 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.^35,36 Dosages 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.⁴² The 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.⁴³ Diabetic 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

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

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

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.⁷² Individuals 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

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

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.

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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.⁸ Conversely, 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.¹¹ For 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

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.¹⁵ Adapalene 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.¹⁸ It 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

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.¹¹ Salicylic 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

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).¹⁰ Currently, 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

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.¹ Children 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.³² This 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.¹ Other 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.¹³ Providers 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).¹ While 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.³ The 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.^1,11 Additionally, 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.¹ Patients 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.⁶³ High-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.²³ The 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.⁶⁵ With 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.

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