Understanding and Addressing Barriers to Glucagon-like Peptide-1 Receptor Agonist Use in Patients with Type 2 Diabetes

INTRODUCTION

Over 37 million people in the United States live with diabetes mellitus.¹ The vast majority (≈90%-95%) of those people have type 2 diabetes (T2D). For those individuals, optimization of glycemic control is key to prevent microvascular complications.² In addition, controlling comorbidities such as hypertension and dyslipidemia to reduce cardiovascular (CV) risk is a crucial standard of care.³ Recent evidence also indicates that use of specific glucose-lowering medications, such as the glucagon-like peptide-1 receptor agonists (GLP-1 RAs), can provide additional benefits, including weight loss and risk reduction for CV disease (CVD).² It is important for all members of the healthcare team, including pharmacists, to understand the current evidence and clinical guidelines for the management of diabetes and its complications, as well as barriers to utilization of preferred diabetes medications. This review will explain the evidence and recommendations that support the early use of GLP-1 RAs, describe comprehensive management strategies to effectively use GLP-1 RAs, and identify barriers to use with approaches to overcome these barriers.

BARRIERS TO UTILIZATION OF GLP-1 RAS

Despite the availability of new and purportedly better treatments for T2D over the last 2 decades, the percentage of people with T2D who are achieving glycemic targets remains relatively unchanged. An analysis of the National Health and Nutrition Examination Survey (NHANES) study group shows that diabetes management improved from 1999 to early 2010s, but then declined from 57.4% in the 2007-2010 period to 50.5% in the 2015-2018 period.⁴ GLP-1 RAs are one of the newer classes of medications to treat T2D, with the first agent, exenatide (Byetta), being approved by the US Food and Drug Administration (FDA) in 2005.⁵ With over a decade of experience, the class should be considered a well-established and effective option for the treatment of T2D, but continued changes within the class as well as advancements with clinical evidence make the GLP-1 RAs a continually evolving, and perhaps elusive, drug class. Despite strong glucose- and weight-lowering effects and a low risk of hypoglycemia, data from the NHANES show that utilization of the newer classes of diabetes medications, including GLP-1 RAs, remains low. Between 2015 and 2018, 82.7% of participants with diabetes were prescribed a glucose-lowering medication but GLP-1 RAs or sodium-glucose cotransporter 2 (SGLT2) inhibitors accounted for only 7.1% of those prescriptions.⁴

Current professional practice guidelines recommend preferred use of GLP-1 RAs in patients with T2D and atherosclerotic CVD (ASCVD) independent of glucose control or other medication use.³ This evidence is discussed in more detail later in this review and in the first monograph in this series, Updates in Glucagon-like Peptide-1 Receptor Agonist Use for Patients With Type 2 Diabetes to Maximize Glycemic and Non-Glycemic Outcomes. Despite this recommendation, 2 large observational studies (1 using an ongoing US-based registry and 1 using a large administrative claims database) found that less than 8% of individuals with T2D and ASCVD were prescribed a GLP-1 RA.^6,7 A study evaluating 21,173 patients with T2D and ASCVD within an academic medical center found that only 1.6% of patients received a GLP-1 RA.⁸ Another study from the Department of Veterans Affairs (VA) found that only 8% of patients with T2D and ASCVD received a GLP-1 RA.⁹ While cost is often cited as a primary reason for why GLP-1 RAs are not used, the copay amounts in the VA system were generally low. This suggests that other factors beyond cost contribute to low utilization of the GLP-1 RA class.

There are also racial, ethnic, and socioeconomic inequities in GLP-1 RA use in the United States. In a large retrospective cohort analysis of over 1 million patients with T2D, the overall percentage of patients treated with a GLP-1 RA was low (3.2%-10.7% from 2015-2019), and similar among patients with T2D and ASCVD (2.8%-9.4% from 2015-2019). Importantly, lower rates of use were found in Asian, Black, and Hispanic patients with T2D, whereas female sex and higher household incomes were associated with higher GLP-1 RA use.¹⁰ In patients with T2D and ASCVD in the VA, non-Whites were also less likely to receive a GLP-1 RA.⁹

Clinical studies that identify barriers specific to the use of GLP-1 RAs are scarce. Barriers to diabetes treatment, in general, have included those at the provider level, the patient level, and the system level.¹¹ Provider-level barriers may include lack of knowledge of new evidence and guideline recommendations, treatment complexity, time and resource constraints, competing demands, or perception of side effects. When considering provider-level barriers, it is worth noting that less than 15% of diabetes care is provided by endocrinologists.¹² Most patients with diabetes are managed by primary care providers, but many patients with comorbidities are managed by other specialists, including cardiologists. Patients with both T2D and ASCVD are 4 times more likely to see a cardiologist than an endocrinologist.¹³ A recent study of cardiologists found that only 20% felt very familiar with the outcomes data for GLP-1 RAs and only 5% would initiate a guideline recommended SGLT2 inhibitor or GLP-1 RA for a patient after an acute coronary syndrome.¹⁴ This may be explained by a lack of familiarity with these therapies and the perception that management of diabetes is beyond their scope of practice. This evidence illustrates the need to address knowledge gaps for all practitioners who routinely care for people with T2D with or without CVD, including pharmacists.

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Patient-related barriers may include misunderstandings of the condition and/or treatment regimens, concerns for side effects, or motivation. Patient-related barriers are often due to a treatment approach that is not collaborative and not patient-centered. Patient beliefs, values, and preferences play a crucial role in the success of any diabetes treatment plan.¹¹ Making treatment decisions without the patient’s participation can contribute to low adherence and persistence with prescribed regimens. Low adherence and long-term persistence with prescribed regimens remains a barrier that should be addressed.

System-level barriers can include cost of medications, access to care, and socioeconomic inequities. System-level barriers also include inadequate implementation of multidisciplinary teams and lack of effective decision support tools or other population health initiatives. For example, patient-centered medical homes and integrated care delivery systems focus on managing chronic disease at the system level. Decision support tools such as dashboards and disease management pathways

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within an electronic health record can assist providers in making evidence-based therapeutic decisions in real-time. Population care approaches can proactively identify patient populations and assist providers in targeting and caring for patients at risk for poor outcomes. Unfortunately, many people with diabetes in the Unites States are not engaged in their treatment plan or do not have access to care through health systems that use these system-based approaches.¹⁵

Therefore, the underutilization of GLP-1 RAs is likely multifactorial and may include clinician-based knowledge gaps, ineffective use of multidisciplinary teams and system-based processes, as well as limited patient access. To address these barriers clinicians should understand the pharmacology, mechanism of action, efficacy, side effects, and role in therapy of GLP-1 RAs, as well as patient-specific considerations when initiating therapy with a GLP-1 RA. Clinicians should also consider population- and system-based approaches that focus on optimizing care.

ADDRESSING KNOWLEDGE GAPS

Pharmacology of GLP-1 RAs

The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L cells following oral nutrient intake.¹⁶ Activation of GLP-1 receptors stimulates glucose-dependent insulin secretion from pancreatic β cells, suppresses inappropriately elevated glucagon secretion from pancreatic α cells, delays gastric emptying, and induces satiety via a direct action in the central nervous system.¹⁷ Because the therapeutic potential of natural GLP-1 is limited due to rapid degradation by the dipeptidyl peptidase-4 (DPP-4) enzyme, synthetic GLP-1 RAs are DPP-4 resistant.¹⁷

The GLP-1 RA class mimics the action of endogenous GLP-1. They stimulate insulin secretion from pancreatic β cells in a glucose-dependent fashion while reducing the unnecessary release of glucagon from pancreatic α cells during hyperglycemia, which reduces undesired hepatic release of glucose. These agents also directly affect the stomach through the autonomic nervous system to slow gastric emptying, thereby reducing meal-related glucose excursions. Additionally, through the central nervous system, GLP-1 RAs increase satiety, resulting in the patient feeling fuller faster. Collectively, these actions facilitate a reduction in both blood glucose and body weight without intrinsically causing hypoglycemia.^18-20

The benefits of GLP-1 RAs go beyond that of improving blood glucose and body weight. Many large-scale trials have demonstrated protective effects of some long-acting GLP-1 RAs on the heart and kidneys. The mechanism behind these noteworthy outcomes is not yet clear. Current hypotheses for these unique CV benefits include endothelial function improvement, reduced oxidative stress, reduced inflammation in coronary arteries, and possibly improved plaque stability.²¹ Regardless of the mechanism of the proven CV benefits, these outcomes have shifted prescribing patterns and the place in therapy for the GLP-1 RA class.

PLACE IN THERAPY FOR THE GLP-1 RA CLASS

The American Diabetes Association (ADA) 2022 Standards of Medical Care in Diabetes guidelines have modified its approach in recommending pharmacologic therapies for treating T2D over time.^2,3 Rather than focusing solely on anticipated glycemic reduction and adverse drug events, a new emphasis has emerged and is focused on the pre-existing conditions of ASCVD, chronic kidney disease (CKD), and heart failure (HF). This approach is also mirrored in the 2020 American College of Cardiology (ACC) Expert Consensus Decision Pathway on Novel Therapies for CV Risk Reduction in Patients with T2D.²² The ADA 2022 Standards of Medical Care in Diabetes notes that following the implementation of lifestyle modifications, patient-centered aspects should be considered during the selection of initial and subsequent pharmacotherapy, which includes consideration of cost, access to therapy, and management needs. While metformin, with lifestyle modifications, may be the initial pharmacologic option for many patients, consideration of preexisting comorbid conditions may shift treatment selection to alternative agents. Guidelines now consistently recommend initiating a medication with evidence for CV or renal benefit in patients with established CVD, indicators of high CV risk (aged >55 years with coronary, carotid, or lower-extremity artery stenosis >50%, or left ventricular hypertrophy), CKD, or HF regardless of their glycemic control and at the time the compelling indication emerges. Thus, considering the presence or absence of compelling pre-existing conditions is necessary to best guide the selection of initial and add-on glucose-lowering therapies.²²

When ASCVD Predominates

The CV outcome trials of the GLP-1 RAs are summarized in Table 1.^23-28 Dulaglutide, liraglutide, and subcutaneous semaglutide all demonstrated benefit in reducing the primary composite endpoint of major adverse CV outcomes (MACE), while lixisenatide, exenatide extended release (XR), and oral semaglutide demonstrated safety, but not benefit.^23-28 The CV outcome trials evaluating SGLT2 inhibitors also saw benefit with canagliflozin, dapagliflozin, and empagliflozin.^29-31 Therefore, the ADA gives no preference between using an SGLT2 inhibitor or a GLP-1 RA to reduce the risk of MACE in patients with established ASCVD or indicators of high CV risk. However, other considerations may guide selection.

SGLT2 inhibitors predominately reduce the risk of MACE in patients with established ASCVD rather than in patients with only high CV risk factors.³² Similarly, GLP-1 RAs also demonstrate a greater reduction of MACE in patients with established ASCVD compared with those with only risk factors; however, patients with only CV risk factors also experience benefit, yet to a lesser degree.³³ Thus, while no preference should be given for a GLP-1 RA versus an SGLT2 inhibitor when used for secondary CV prevention, patients with high-risk factors for CVD may benefit from early initiation of a GLP-1 RA.

While the overall reduction of MACE is similar between the 2 classes, particularly for those requiring secondary prevention, the individual outcome components of MACE (stroke, myocardial infarction, and CV death) vary among the CV outcome trials. Most notable is the secondary outcome of non-fatal stroke. Although not statistically significant in each CV trial, the reduction in the occurrence of stroke is consistent among the long-acting GLP-1 RA CV trials (Table 1).^25-27 In fact, the American Heart Association/American Stroke Association 2021 Guideline for Secondary Prevention of Ischemic Stroke endorsed the use of a GLP-1 RA in patients with established ASCVD, including ischemic stroke.³⁴ SGLT2 inhibitors do not show the same consistent benefit for this secondary outcome.³⁵ Thus, a long-acting GLP-1 RA may be preferred in patients who have had a stroke.

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When HF Predominates

Unlike when ASCVD predominates, there is clearly a greater benefit for the use of the SGLT2 inhibitor class over the GLP-1 RA class when HF is the primary focus of concern. Large-scale studies comparing the addition of an SGLT2 inhibitor with the standard-of-care treatment have evaluated rates of hospitalization for HF (hHF) in patient populations with HF with reduced ejection fraction (HFrEF)^36,37 or HF with preserved ejection fraction (HFpEF),³⁸ with and without T2D. CV-focused trials also have documented rates of hHF as a secondary outcome to MACE in adults with T2D, but low rates of pre-existing HF (10%-25%).^29-31 Each study demonstrated an approximate 30% relative risk reduction for hHF. Thus, SGLT2 inhibitors not only reduce hHF in patients with pre-existing HFrEF or HFpEF, but they also delay the development of HF in those without the condition. GLP-1 RAs have not demonstrated the same robust benefit on HF outcomes. For this reason, the ADA 2022 Standards of Medical Care in Diabetes recommends an SGLT2 inhibitor when HF predominates.^2,3

When CKD Predominates

Similar to when HF predominates, the presence of CKD should stimulate the preferential selection of an SGLT2 inhibitor over a GLP-1 RA. Two large-scale kidney outcome trials evaluated the addition of an SGLT2 inhibitor to standard-of-care treatment in populations with or without T2D and a medical history of decreased estimated glomerular filtration rate (eGFR) and proteinuria.^39,40 The primary composite outcomes were generally first occurrence of any of the following: onset of end-stage kidney disease, doubling of the serum creatinine or 50% decline in eGFR, or death from kidney or CV disease. Both studies were stopped early on account of a statistically significant 30% to 39% relative risk reduction for the primary composite endpoint.Upon further analysis, every component of the primary composite outcome also reached statistical significance, including a notable slowing in the rate of eGFR decline. A third SGLT2 inhibitor was similarly investigated in patients with CKD and also stopped early; however, the results have not yet published in full.⁴¹ Secondary kidney endpoints from several of the SGLT2 inhibitor CV outcome trials also suggested benefit of SGLT2 inhibition on progression of CKD.^29-31 Secondary kidney outcomes reported with agents from the GLP-1 RA class suggest a benefit, particularly related to reduced proteinuria, although primary kidney outcome data are currently lacking (Table 1).^24,25,29

SELECTING THE BEST GLP-1 RA FOR THE PATIENT

Consider the following factors when selecting the best GLP-1 RA for a given patient: glycemic impact, weight reduction, CV risk reduction, kidney benefits, route and frequency of administration, and safety and tolerability profiles. Delivery devices may also influence product selection.

Within Class Comparison of GLP-1 RAs

Presently, 7 GLP-1 RAs are available in the United States, not including the new dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) product, tirzepatide (Mounjaro, approved 2022),⁴² which was discussed in detail in Module 1. The products in the GLP-1 RA class are divided into 2 pharmacokinetic categories: short- and long-acting agents (Table 2).^5,43,45-49 Given the limited duration of action of exenatide (Byetta, approved 2005)⁵ and lixisenatide (Adlyxin, approved 2016),⁴³ these short-acting GLP-1 RAs must be taken before meals to render their glycemic benefit of blunting the postprandial rise influenced by carbohydrate ingestion with a minimal impact on fasting blood glucose.¹⁶These products are ideal for patients who need a focused impact on the post-meal glycemic index. Their overall hemoglobin A1C (A1C) reduction ranges from 0.4% to 1.1% (Table 3).⁵⁰ Lixisenatide is also available as a fixed-dose combination with basal insulin glargine (U-100; Soliqua 100/33, approved 2016) for dual coverage of fasting and postprandial blood glucose.⁴⁴

Long-acting GLP-1 RAs include liraglutide (Victoza, approved 2010),⁴⁵ dulaglutide (Trulicity, approved 2014),⁴⁶ exenatide XR (Bydureon, approved 2012; BCise pen, approved 2017),⁴⁷ and injectable and oral semaglutide (Ozempic, approved 2017, and Rybelsus, approved 2019, respectively).^48,49 Long-acting agents result in a more consistent activation of GLP-1 receptors, allowing for once-daily, or at times, once-weekly administration.¹⁶ While most GLP-1 RAs are administered subcutaneously, an option for patients deterred by injectable therapies is daily oral semaglutide. Although considered a long-acting product, it must be taken on an empty stomach with no more than 4 oz of water at least 30 minutes before breakfast to allow for adequate absorption.⁴⁹ For patients unable to take oral semaglutide or a short-acting GLP-1 RA as instructed before meals, a long-acting injectable GLP-1 RA may provide a more flexible timing of administration because they can be taken at any time of day, with or without food. Compared with short-acting GLP-1 RAs, the longer-acting products are associated with a more balanced impact on reducing both postprandial and fasting glucose and provide a greater reduction in A1C, ranging from 0.6% to 2.2% depending on the product and dose (Table 3).⁵⁰As such, the long-acting GLP-1 RAs are preferrable for patients who want a greater A1C decline and more convenient administration. Similar to lixisenatide, long-acting liraglutide is also available in a fixed-dose combination with basal insulin degludec (U-100; Xultophy, approved 2016), which may also prove convenient for patients who want a long-acting GLP-1 RA and an ultra–long-acting basal insulin.⁵¹

Preparation steps, administration, and storage requirements differ among the products; therefore, each GLP-1 RA requires product-specific counseling and self-administration education (Table 4).^5,43,45-49 Some pens are single-use devices, whereas others are multiuse devices. Some devices require the attachment of a pen needle, whereas others come with the needle already connected. Oral semaglutide must be stored in the original container until right before the tablet is ingested. Tablets cannot be stored in a pill organizer or other container.⁴⁹ These differences in delivery devices may influence a patient’s preference, accuracy, and usability among the available products.⁵² Therefore, shared decision-making should continue to guide the selection of the best GLP-1 RA for each patient.

Comparison of GLP-1 RAs by Weight Loss

Weight reduction is another noteworthy consideration that may influence GLP-1 RA product selection for a given patient. A class-wide effect, the impact of weight loss varies with the shorter-acting products resulting in a smaller weight loss benefit (+0.3 kg to -2.96 kg) compared with the long-acting products (+0.3 kg to -6.5 kg). Weight reduction accumulates over months of continued use with a dose-dependent effect. Based on several head-to-head studies, it appears that long-acting GLP-1 RAs induce more weight loss than short-acting agents.⁵³ Weekly injected semaglutide appears to lead to greater weight loss than daily oral semaglutide, although these products have not been directly compared (Table 3).⁵⁰ Furthermore, both injected semaglutide and liraglutide are indicated by the FDA specifically for weight reduction at doses higher than those used to manage T2D.^54,55

Safety and Tolerability Considerations

The tolerability profile of GLP-1 RAs primarily includes side effects that are gastrointestinal (GI) in nature.⁵⁶ These include nausea, vomiting, and diarrhea, which are typically mild to moderate in intensity and occur shortly after treatment initiation or dose escalation but are transient with continued use. Of note, the short-acting agents, exenatide and lixisenatide, have higher rates of GI adverse events (AEs) due to their greater impact on slowing gastric emptying. Of the long-acting GLP-1 RAs, exenatide XR has the lowest rates of GI-related symptoms (Table 3).⁵⁰ Given the pharmacodynamic impact on gastric motility, those with a history of significant gastroparesis should avoid use of drugs in the GLP-1 RA class. Other disadvantages that may limit use of GLP-1 RAs include injection site reactions, exacerbated diabetic retinopathy, the potential risk of acute pancreatitis, and the black box warning regarding thyroid c-cell tumors. While some GLP-1 RAs are not recommended for use in patients with a creatinine clearance of less than 30 mL/min or with end-stage kidney disease,^5,43,47 other agents do not require specific dosage adjustments based on kidney function.⁴⁶

MANAGEMENT OF GLP-1 RA THERAPIES

Adjusting Background Therapies

At times, the addition of a GLP-1 RA may require alterations to other antihyperglycemic medications that a patient is taking due to the treatment-emergent risk of hypoglycemia, despite the low inherent risk of hypoglycemia with GLP-1 RA monotherapy. Specifically, practitioners should consider the need to adjust background therapies when adding a GLP-1 RA to a sulfonylurea or insulin therapy.⁵⁷ While evidence clearly supports the addition of a GLP-1 RA for many reasons, including CV risk mitigation and weight loss, less direction exists regarding how to adjust background therapies when initiating a GLP-1 RA. The following recommendations can be used to adjust background therapies in a patient starting a GLP-1 RA, with the approach individualized based on the specific needs of each patient.

Addition of a GLP-1 RA to Background Basal Insulin Therapy

Adding a GLP-1 RA to an insulin regimen can balance weight gain caused by the insulin therapy while facilitating the achievement of individualized glycemic targets. When adding a GLP-1 RA, adjustment of the background insulin dose is necessary at times to avoid hypoglycemia. For patients with an A1C of 8.0% or lower on a stable basal insulin regimen, consider empirically reducing the insulin dose by approximately 20% when starting a GLP-1 RA.^58-61 For those with an A1C of more than 8.0%, the GLP-1 RA can be reasonably initiated without adjusting the basal insulin dose for many patients. However, in those with a history of severe hypoglycemia and/or hypoglycemia unawareness, it may be prudent to reduce the basal insulin dose to err on the side of safety regardless of their current A1C level. Following GLP-1 RA initiation at the lowest dose with subsequent titration, the basal insulin dose should be titrated based on clinical response and as informed by blood glucose monitoring data.

Addition of a GLP-1 RA to Background Bolus Insulin Therapy

Adjustment of background mealtime insulin is also important to prevent hypoglycemia when starting a GLP-1 RA. In patients with a history of hypoglycemia or those at, near, or below glycemic goals, it is reasonable to decrease background prandial insulin doses by 50% or even hold the prandial insulin altogether when starting a GLP-1 RA. Eventual discontinuation or dose titration of the prandial insulin can then be informed by the patient’s response to therapy and blood glucose monitoring data. In approximately 50% of patients with T2D receiving basal/bolus insulin, the addition of a once-weekly GLP-1 RA allows for discontinuation of mealtime insulin over time.⁶²

Addition of a GLP-1 RA to Background Sulfonylurea Therapy

It is also prudent in many cases to hold or reduce the dose of background sulfonylurea therapy when starting a GLP-1 RA. An initial 50% dose reduction is likewise reasonable in many patients.^63,64 It is often possible to eliminate the sulfonylurea altogether, which can be advantageous in terms of avoiding hypoglycemia, minimizing the complexity of the diabetes regimen, and augmenting the weight loss benefits of the GLP-1 RA. Whether it is decided to initially decrease the dose or hold the background sulfonylurea altogether, continued use and titration of the sulfonylurea should be informed by patient response and blood glucose monitoring data.

Addition of a GLP-1 RA to Background DPP-4 Inhibitor

GLP-1 RAs and DPP-4 inhibitors both work to augment the impaired incretin response present in people with T2D. While using a DPP-4 inhibitor with a GLP-1 RA does not pose a safety concern for patients, there is no evidence supporting additional efficacy with this combination, thus combined use is not recommended.² If initiating a GLP-1 RA in a patient with T2D who is taking background DPP-4 inhibitor therapy, it is recommended that the DPP-4 inhibitor be discontinued.

Interchanging One GLP-1 RA for Another

At times interchanging one GLP-1 RA for another may be preferred. Reasons for this may include the desire for greater efficacy, improved tolerability, CV benefit, an alternative dosing frequency or route of administration, or a lower cost and formulary restrictions. The rationale for the interchange will provide direction for how to discontinue the initial GLP-1 RA and begin the new GLP-1 RA.

If switching is prompted by GI AEs, discontinue the first GLP-1 RA and wait for symptoms to resolve. After selecting a GLP-1 RA with a better AE profile related to GI disturbances, initiate the new product at the lowest dose. Also consider a slower dose titration to allow for improved acclimation to the therapy. If the GLP-1 RA interchange is prompted for another reason, discontinue the first GLP-1 RA, select the new GLP-1 RA with the desired characteristics, start with an equivalent dose, and titrate accordingly.^65-67 If switching from a once-daily or twice-daily product, give the first dose of the new product on the day after discontinuation. If switching from a once-weekly product, give the first dose of the new product 7 days after discontinuation (Table5).^65-67

When switching GLP-1 RAs, take time to educate the patient about the new product. Because each injectable GLP-1 RA is delivered in a unique pen, patients may not be familiar with the new delivery device. It is especially important to advise patients when switching from a single-use pen to a multiuse pen to ensure they retain the device for subsequent doses.

Avoiding Drug Interactions

Drug interactions with GLP-1 RAs can occur through the impact of delayed gut motility, additive glycemic reductions, or absorption hindrances of products with low bioavailability or narrow therapeutic indices. This concern is most impactful for patients taking both oral semaglutide and levothyroxine or an oral bisphosphonate, which are all advised to be taken each morning on an empty stomach without food or significant drink.⁴⁹ One solution is to move levothyroxine administration from morning to bedtime, at least 3 hours after the evening meal.⁶⁸ Additionally, selecting a once-weekly or once-monthly oral bisphosphonate can reduce the frequency of administration issues.

Although drug interactions with injectable GLP-1 RAs exist, none have proven, clinically meaningful consequences, including interactions with orally administered acetaminophen, digoxin, warfarin, oral contraceptives, metformin, statin, angiotensin-converting enzyme inhibitors, and griseofulvin.⁶⁹ However, if the patient is still concerned about the interaction, taking the oral product 1 hour before injecting the GLP-1 RA may help mitigate any real interaction. Lastly, although GLP-1 RAs do not inherently cause hypoglycemia, the risk may precipitate when they are combined with a sulfonylurea or insulin. Therefore, a dose reduction of the alternative agent may be necessary. Adjustment of background therapy when adding a GLP-1 RA is described in greater detail above.

OVERCOMING BARRIERS OF GLP-1 RAS AND ENSURING PATIENT UNDERSTANDING

Adherence and persistence are particularly challenging with the GLP-1 RAs. Several barriers to consistent use of these agents include clinical inertia, cost, GI AEs, and injection concerns. These issues underscore the need for better provider-patient communication to appropriately set expectations, discuss the patient’s willingness and ability to take the medication, and address additional barriers that may arise.⁷⁰ Several real-world studies have demonstrated variability in patient preference, adherence, and persistence among GLP-1 RA agents. Higher adherence and persistence rates have been demonstrated with dulaglutide than with exenatide XR and liraglutide⁷¹; higher adherence has been demonstrated with exenatide XR than with exenatide and liraglutide^72,73; and higher patient preference has been demonstrated with dulaglutide than injectable semaglutide.^52,74 Finally, once-weekly GLP-1 RAs have been associated with higher adherence and persistence compared with daily injections with GLP-1 RAs.⁷⁵

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Avoiding the Stigma of Injectable Agents

Because products in the GLP-1 RA and insulin classes are predominately injected, it is understandable how patients may not appreciate that GLP-1 RAs are not insulin. Historically, a negative stigma has been associated with insulin use,^76-80 which may hinder some patient’s willingness to start an injectable treatment, especially earlier in their diabetes care. For this reason, it is imperative that patients are educated that GLP-1 RAs are not insulin, and conversely provide benefits, unlike insulin. Educate patients that in addition to glycemic control, GLP-1 RAs provide weight reduction, CV risk reduction, and some kidney protection while not independently inducing hypoglycemia. Knowledge of these additional benefits may help ensure patients continue using the GLP-1 RA over time. Similarly, advise patients that GLP-1 RAs should not be used as-needed; unlike bolus insulin, the benefits of GLP-1 RAs accumulate with continued use and thus must be scheduled to achieve maximal benefit. Any benefits gained while using a GLP-1 RA will be lost if the product is discontinued.

Managing Patient Expectations

Most of the GLP-1 RAs have recommended lower doses for initiation of therapy, followed by titration to higher doses if needed for glycemic control. This dose titration is designed to minimize dose-related GI AEs.

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Educate patients to not expect immediate changes in their blood glucose values, especially when initiating GLP-1 RA therapy, because the lower starting doses provide more mild glycemic reductions. However, greater glycemic benefits are achieved as the dose is increased. Long-acting GLP-1 RAs can take up to 2 to 4 weeks to begin lowering fasting and postprandial blood glucose values. Short-acting GLP-1 RAs lower blood glucose in a matter of days; however, patients should be advised to monitor the change in their postprandial blood glucose. If patients are dose-reducing background insulin therapy, their blood glucose may temporarily increase because the impact of insulin is faster than the onset of GLP-1 RAs. Likewise, changes in body weight are also gradual but continue occurring for months after initiation of the GLP-1 RA, with increased efficacy after each dose titration. Remind patients that the efficacy of reducing their blood glucose and body weight, as well as the possible emergence of some adverse drug events, will increase with each dose escalation, but that not all dosage increases will render the same intensity of outcomes.

Advise patients proactively that GI AEs are the most bothersome side effect but are typically mild to moderate in intensity and diminish with continued use. Patients can mitigate the occurrence of these AEs by eating small meals, eating slowly, and no longer eating once full. Doing so will help prevent the development of nausea.

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Utilizing Pharmacists in Multidisciplinary Team Care

Successful and sustainable diabetes care requires a multidisciplinary approach (Figure 1). With the shortage of endocrinologists, primary care providers, and certified diabetes care and education specialists, pharmacists are well-positioned to serve as crucial members of the diabetes management team. Pharmacists can improve outcomes in many ways. Pharmacists can conduct comprehensive medication reviews, assess adherence, and provide patient education to improve medication adherence, effectiveness, and tolerability. Pharmacists can improve access to medications by helping patients through the prior authorization process and manufacturer assistance programs.

Pharmacists can provide direct patient care services through collaborative practice agreements. They can help combat clinical inertia by following up with patients in between provider visits to optimize the use of medication therapies and to make sure patients are on guideline-recommended treatment options. Pharmacists can also be team members within their practice or healthcare system that focus on system-based approaches to target poor performing metrics. The following scenarios provide examples of ways in which a pharmacist could improve GLP-1 RA utilization.

Scenario #1:

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A pharmacist that works in an internal medicine clinic provides diabetes management through a collaborative practice agreement. Through a population health initiative, he audits the clinic's population of patients who have both T2D and ASCVD and identifies that only 10% of that population is prescribed a GLP-1 RA. He develops a comprehensive plan to increase use of medications known to reduce the risk of MACEs, which includes provider education and a clinical decision support tool to aid providers in selecting and prescribing preferred medications.

Scenario #2: A large family medicine clinic completes an audit of their T2D population and determines a large percentage of patients initially prescribed a GLP-1 RA never start the medication or do not remain on the medication long-term. The team members identify a gap in adequate patient education and support at the time of GLP-1 RA initiation. The team decides to implement a process that sends a message through the electronic health record for the clinical pharmacist team member to call the patient 2 weeks after initially prescribing a GLP-1 RA to assess access and tolerability and to answer questions about issues such as administration, side effects, and dose titration.

The utilization of pharmacists in the patient care team can improve overall care and achievement of outcomes, including the achievement of glycemic targets and stronger adherence to clinical practice guideline recommendations. A study evaluating a pharmacist-managed diabetes program in a primary care setting showed a greater reduction in A1C as well as a higher percentage of patients achieving the Healthcare Effectiveness Data and Information Set (HEDIS) goal of an A1C lower than 8% in the group managed by a clinical pharmacist compared with usual care.⁸¹ Another study in the primary care setting found that the collaboration of pharmacists and physicians was associated with a reduction in A1C of 1.75% compared with 0.16% with usual care (P < .001) and a lower rate of emergency department visits and hospitalizations, resulting in an estimated cost savings of $633,015.⁸² A recent review of pharmacist-managed diabetes programs describes several pharmacist care models in a variety of practice settings and highlights the outcomes associated with pharmacist care, as well as opportunities to expand pharmacy services.⁸³ Although these studies clearly show the value that pharmacists can make in improving diabetes outcomes, additional studies are needed to evaluate the utilization of pharmacists to achieve outcomes beyond HEDIS measures, including the improvement in percentage of patients prescribed medications according to guideline recommendations to reduce major adverse outcomes.

CONCLUSION

GLP-1 RAs are an important therapeutic option for patients with T2D to not only improve glucose control and facilitate weight loss, but also to reduce CV and kidney risk, with a low-risk of causing hypoglycemia. It is appropriate to consider initiating a GLP-1 RA early in the course of the disease given these noteworthy benefits. Pharmacists can play a critical role as members of the diabetes management care team by identifying the best GLP-1 RA for a given patient, recommending appropriate background therapy adjustments, providing medical education to overcome barriers and improve medication adherence, and facilitating medication titration as appropriate per patient response.

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