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

Term	Definition
In vivo gene therapy	Administered directly into patients by injection
Ex vivo gene therapy	Cells are removed from patients, genetically modified, and re-introduced into patients
Adeno-associated virus (AAV) vector	Genetically modified virus commonly used to deliver gene therapy in vivo
Capsid	Outer icosahedral (20 roughly triangular facets arranged in a spherical or spherical-like manner) protein shell of the virus/viral vector
Serotype	Distinct variation between viral capsids within a species based on surface antigens (e.g., AAV serotype 9 [AAV9])
Host	Gene therapy recipient
Tropism	A virus’s specificity for a particular host tissue, likely driven by cell-surface receptors on host cells
Target tissue	Tissue/organ/cell type intended for genetic correction
Gene of interest (GOI)/ transgene	Gene that needs to be fixed
Expression cassette	GOI plus DNA sequences to make it function, including a promoter
Inverted terminal repeat (ITR)	DNA sequences that flank the GOI as part of the expression cassette; required for genome replication and packaging; the ITR-flanked transgene forms a circular structure (episome)
Episome	Self-contained and self-replicating circular DNA that contains the expression cassette; stays in the cell’s cytoplasm and does not become part of the cell’s chromosomes
cap	Gene that encodes the proteins comprising the virus capsid
rep	Gene that encodes replicase proteins required for virus replication and packaging
Neutralizing antibodies (NAb)	Antibodies that bind to specific areas of viral vector capsids to block uptake by host cells
Vector genomes/kilogram of patient body weight (vg/kg)	Common terminology for vector dosing; sometimes referred to as genome copies (gc) per kilogram

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

Strategy	Rationale	Potential Advantages	Potential Disadvantages
AAV capsid engineering	Remove or alter NAb-binding epitopes	·  Allow dosing with pre-existing NAb ·  Allow redosing	·  Complex, expensive, lengthy process ·  May alter tropism to target tissue ·  May require patient screening to determine what epitopes to modify
Direct administration to appropriate tissue	Minimizing systemic exposure may minimize immune response	·  Reduced toxicity after gene therapy administration	·  Not possible for all indications
Plasmapheresis	Reduce amount of all immunoglobulins in a patient	·  Allow dosing with pre-existing Nab ·  Allow redosing	·  Invasive procedure ·  Not specific for capsid antibodies ·  May increase infection risk due to reduced circulating antibody
Capsid decoys	Pretreat patient with empty capsid to ‘absorb’ capsid-specific antibodies	·  Allow dosing with pre-existing Nab ·  Allow redosing	·  Depending on clearance time for empty capsid-NAb complexes, may increase the total capsid burden and enhance immune response
IdeS	Degrades all IgG	·  Allow dosing with pre-existing Nab ·  Allow redosing ·  Good safety profile in transplant patients	·  Patient may have pre-existing antibodies to IdeS that could induce an immune response ·  Patient may develop antibodies to IdeS, so may not be able to be used more than once ·  Not specific for anti-AAV IgG ·  Increased infection risk due to reduced circulating IgG
Immunosuppression	Overall or cell type-specific suppression of the immune response	·  Reduced toxicity after gene therapy administration	·  Can have adverse effects, especially if used long term ·  Increased infection risk

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.

 

 

Download CE Activity

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

Social Communication Deficits

Restricted/Repetitive Behaviors

1) Deficits in social-emotional reciprocity ·        Reduced sharing of interests ·        Struggles with emotional recognition   2) Deficits in non-verbal communication ·        Aversion to eye contact ·        Abnormal body language/facial expressions   3) Deficits in developing, maintaining, and understanding relationships ·        Scripted speech/taking language literally ·        Difficulty in sharing imaginative play ·        Difficulty making friends ·        Absence of interest in peers

1) Stereotyped or repetitive motor movements, use of objects, or speech ·        Arranging objects meticulously ·        Echolalia (meaningless word repetition) ·        Stereotypical movements like hand-flapping   2) Hypo- or hyper-reactivity to sensory input or unusual interest in sensory input ·        Apparent indifference to pain/temperature ·        Adverse response to sounds or textures ·        Excessive smelling/touching of objects ·        Visual fascination with lights or movement   3) Highly restricted, fixated interests that are abnormal in intensity or focus ·        Expecting others to share their interests ·        Strong attachment to unusual objects   4) Insistence on sameness, inflexibility in routines, or ritualized patterns of behavior ·        Discomfort with change

 

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

 

Table 2. Level of Severity of ASD²

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

 

Prognosis

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

 

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

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

 

ASD CASE PRESENTATION

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

 

Strategies for Support

Pharmacists can employ their medication expertise to help the healthcare team, families, and patients improve ASD management. As John’s description indicates, patients with ASD are often sensitive to sensory input like noise, light, and crowded environments.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.”

 

Download CE Activity

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

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

 

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

 

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

 

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

 

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

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

 

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

 

Hypertension

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

 

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

 

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

 

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

 

Hyperlipidemia

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

 

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

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

 

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

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

 

Heart Failure

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

 

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

 

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

 

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

 

Standards of Care recommendations for those with HFrEF and diabetes include an angiotensin receptor/neprilysin inhibitor (ARNI) or ACEi or ARB, beta blockers, mineralocorticoid receptor antagonist, and SGLT-2 inhibitor. In individuals with diabetes and HFrEF, including an ARNI (sacubitril/valsartan) instead of ACEi or ARBs is prudent. It is reasonable to consider treatment with spironolactone among individuals with heart failure with preserved ejection fraction (HFpEF) as well. Clinical trials have shown that treatment with an SGLT-2 inhibitor reduces HF hospitalizations.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

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

 

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

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

 

 

CONCLUSION

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

 

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

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