Oral glucagon-like peptide-receptor agonists (GLP1RA) counseling: comparison with insulin counseling

KEYWORDS:

• Counseling
• diabetes
• GLP-1 RA
• insulin
• oral GLP1 RA
• semaglutide

Medication counseling

The diabetes management landscape is experiencing significant innovation in care, which is welcomed by the patients and health-care professionals across the globe. Novel class of glucose-lowering medications have been developed, with newer therapeutic agents getting approved for management of patients with diabetes [1]. User-friendly modes of administration of these medications apart from reduced frequency of dosing have been developed for medications which were hitherto administered as daily injections.

Table 1. General counseling tips: GRACE

Greet the patient Request permission to manage Assess needs, wishes, and preferences Counsel regarding available options; their advantages and limitations Express wish to ensure both short- and long-term health

The advances in drug formulation have moved hand in glove with a noticeable shift in style of drug prescription. The concept of individualized, person-centric approach has become well engrained in diabetes praxis. An informed and shared decision-making has been adapted as the best practice to improve adherence to medications apart from being a tool to empower the patients [2]. Adequate medication counseling facilitates understanding of the potential benefits, risks, limitations, and caveats associated with the therapy in question Table 1.

Insulin motivation

The role and timing of insulin therapy remain a key discussion point while managing patients with Type 2 Diabetes Mellitus (T2DM). The barriers to insulin therapy, the unwanted emotions related to it, and the ways in which these barriers can be bridged have been discussed in great detail. The DAWN2 (Diabetes Attitudes Wishes and Needs 2) [3] project included a significant focus on the attitude and practices of individuals living with diabetes, their care givers, and health-care providers, toward insulin usage. The Insulin Technique Questionnaire (ITQ) study [4] has explored insulin technique practices and injection-related outcomes in patients with type 1 and type 2 diabetes, while exploring perceptions of educators as well.

Injectable GLP-1RA motivation

The emergence of newer non-insulin injectable therapies, however, led to a realization that traditional insulin motivation strategies may not be applicable while counseling patients with T2DM. Injectable glucagon-like peptide 1 receptor agonists (GLP-1RA) have a different mechanism of action, clinical effects, potential side effects, and contra-indications, as compared to insulin. Hence, the style of motivational interviewing and medication counseling needs to be adapted taking into account these significant differences in mode of action, potential benefits as well as the side effect profiles [5]. Nevertheless, with the advent of once-weekly GLP-1RAs like injectable semaglutide and dulaglutide, patients are easily motivated to start the therapy as compared to once-daily injectables viz. liraglutide or lixisenatide.

Oral semaglutide

Recently, an oral GLP-1RA, semaglutide, has been approved for use, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes. The PIONEER program evaluated oral semaglutide in T2D patients of duration ranging from 3.5 to 15 years, from monotherapy through to insulin add-on, in global populations and two trials dedicated to Japanese patients. Oral semaglutide demonstrated consistent and clinically relevant reductions in HbA1c and body weight across all trial population irrespective of race or ethnicity [6]. Oral semaglutide (7 or 14 mg/day) is effective in lowering blood glucose and bringing a reduction in glycosylated hemoglobin (HbA1c) levels. At the same time, this novel GLP-1 RA offers superior weight reduction as compared to liraglutide [7]. It is worth noting that in head-to-head comparison trial, oral semaglutide 7 mg and 14 mg was observed to be superior to sitagliptin 100 mg for HbA1c reduction [8]. A similar superiority in improving glycemic control was noted with 14 mg semaglutide as compared to empagliflozin 25 mg [9] Table 2.

Most importantly, oral semaglutide substantially improved quality-adjusted life expectancy versus empagliflozin, sitagliptin, and liraglutide and was found to be cost-effective versus empagliflozin and sitagliptin, and dominant versus liraglutide, for treating T2DM [10]. In the pre-approval CV outcome trial PIONEER 6, oral semaglutide 14 mg was non-inferior to placebo for the incidence of first major adverse cardiovascular event (MACE) and had demonstrated a lower incidence of CV-related death (HR = 0.49 [95% CI 0.27–0.92]) and all-cause death (1.4% vs 2.8%; HR = 0.51 [95% CI 0.31–0.84]) versus placebo [10]. Nevertheless, we must appreciate that GLP-1RAs and SGLT2 inhibitors work via different mechanisms and both have benefits on metabolic-cardiovascular-renal disease in T2D patients. In line with the recent evidences and guidelines, GLP-1 RA is recommended in T2D patients with/without established CV disease but with the presence of specific indicators of high risk whereas SGLT2 inhibitors are recommended in T2D patients with heart failure, particularly those with HFrEF, to reduce hHF, MACE, and CVD death, as well as in T2D patients with CKD or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g, to prevent the progression of CKD, hHF, MACE, and cardiovascular death [11].

Pre-prescription assessment

In clinical practice, a detailed clinical evaluation remains a key pre-requisite prior to any therapeutic intervention. This helps identify the indication for oral semaglutide use apart from excluding possible contraindications for the therapy. These contraindications include Type 1 Diabetes Mellitus (T1DM), diabetic ketoacidosis, pancreatitis, medullary thyroid carcinoma (MTC), multiple endocrine neoplasia syndrome type 2 (MEN 2), and/or family history of MTC. Pregnancy, preconception planning, lactation, and age <18 years are the physiological phases of life when semaglutide therapy should be avoided.

Diabetic proliferative retinopathy remains another condition where caution may be needed. There was an increased incidence of diabetic retinopathy complications (DRC) with injectable semaglutide vs. placebo in SUSTAIN 6 trial. On the contrary, no variation in DRC adverse events was noted across the SUSTAIN 1 to 5 and Japanese trials. The increased DRC in SUSTAIN 6 may be ascribed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had preexisting DR and poor glycemic control at baseline, and who were treated with insulin [12]. Nevertheless, patients with proliferative retinopathy or maculopathy requiring acute treatment were not included in the PIONEER trials. The incidence of diabetic retinopathy identified during the PIONEER trials was similar to that seen with placebo and active comparators [6]. Clinical evaluation may help to diagnose conditions such as autonomic gastroparesis, which may warrant cautious use and close monitoring of the patients, especially during the initial few weeks after initiation of semaglutide therapy.

Inform, incubate, initiate

The global distribution of health-care resources remains inequitable. It is not uncommon for the patients to bear all health-care expenses, especially in developing nations. In these health-care systems, it is even more important that clinicians and patients partake in shared informed decision-making with the patient if oral semaglutide is deemed as a suitable therapeutic option, while remaining sensitive to implications of cost of therapy not only on the individual but to the entire family. Such complex decision-making might not be possible during the first patient visit, especially considering the limited time available to carry out clinical evaluation as well as to deal with patient concerns. To handle this, we suggest the 3 I strategy (Inform, Incubate, Initiate) [13]. This approach, based on Prochaska’s theory of motivation, allows the individual to remain in contemplation phase for an optimal time. This, in turn, facilitates long-term adherence to suggested therapy.

Oral semaglutide counseling

Medication counseling for oral semaglutide should cover the following details:

1. Potential glucose-lowering, macrovascular, microvascular, and viscero-metabolic effects

2. Mode of administration and caveats to be considered

3. Clinical and biochemical monitoring required

4. Expected side effects and steps for their mitigation

Expected benefits

In most cases, insulin is prescribed for symptomatic relief and glucometabolic control. While insulin is safe for cardiovascular health, the prime reason for using insulin is good glucose control. The macrovascular and microvascular benefits that accrue from insulin use are due to good glucose control and the glycemic legacy which it creates.

With GLP-1RA in general and oral semaglutide in specific, the aim of therapy is multi-fold. This mode of treatment offers not only glucometabolic benefit, but vasculo-and viscero-metabolic benefit as well. The added advantage of weight loss, along with glucose control, distinguishes semaglutide from traditional glucose-lowering medications like insulin [14].

Mode of administration

Oral semaglutide is administered as a once-daily oral dose of either 3 mg, 7 mg, or 14 mg. The lowest dose of 3 mg is intended for initiation, and is not designed for glucose control. The aim of the ‘START LOW, GO SLOW’ dose escalation is to minimize side effects and promote adherence to therapy. After a month on 3 mg, the dose is increased to 7 mg. If adequate control is not achieved after 30 days, a 14-mg dose can be prescribed [6].

The tablet should be stored in a dry place, between 68° and 77°F (20–25°C). The blister pack must not be cut; rather, the tablet should be pushed out and swallowed whole, on an empty stomach, with a sip of water. Not more than 120 ml of water should be taken with the tablet, and breakfast should not be consumed within 30 to 60 minutes of the tablet. A tablet-meal gap of >30 minutes may increase the absorption of semaglutide.

There is no specific guidance for timing of administration of early morning concomitant medication such as L-thyroxine. Wherever possible, a 30-min gap should be ensured between oral semaglutide and other medications. Patients should be counseled to avoid concomitant use of herbal or over-the-counter complementary medicines, as their uncertain composition may lead to unexpected effects.

In case a dose of semaglutide is missed inadvertently, it should not be taken during the day. Rather, it can be skipped, and the next dose can be taken at the appropriate time the following day.

Monitoring

Glucose monitoring is not required on a daily basis with oral semaglutide. The frequency of glucose monitoring will depend upon the clinical situation including urgency of control, expected risk of hypoglycemia, and concomitant therapy being provided. A weekly or fortnightly self-monitoring of blood glucose (SMBG) can be suggested to stable patients, based on their motivation level. Guidance regarding SMBG with once-weekly GLP-1RA can be extrapolated to oral semaglutide [15].

Expected challenges

Nausea, loss of appetite, vomiting, and diarrhea may be experienced initially. Patients should be informed to expect mild nausea which is usually transient and self-limiting. They should be told this is an ‘effect,’ of rather than a ‘side effect’ the drug. In a randomized trial, transient nausea with liraglutide 3.0 mg was related with more noteworthy weight reduction, although symptoms were well tolerated without any diminishing effect on the quality of life improvements [16]. We advocate eating small frequent meals consisting of light, bland foods, at a slow speed, as a strategy to mitigate nausea. Multiple small servings have been adapted as a dietary scheme to reduce nausea and vomiting in diabetic gastroparesis with previous reports recommending a stepwise 6-divided diet in those patients with severe nausea and vomiting [17]. Spicy, fried, hot, or sweet foods should be avoided [5]. Clear and ice-cold drinks, such as zero-calorie carbonated drinks, buttermilk, and lemonade are encouraged.

The cost of semaglutide may be a challenge for some patients, and must be discussed during counseling.

Pragmatic approach

While sharing information about oral semaglutide, the expected vasculo-metabolic and viscero-metabolic benefits of this novel GLP-1RA should be explained in detail. The expectations associated with the use of a medication which can potentially induce weight loss need to be discussed in a realistic and empathetic manner [5]. It must also be explained and reinforced that oral semaglutide, or any other medication, is not a substitute for diet and exercise.

Conclusion

In conclusion, proper tailor-made counseling will essentially play a crucial role in the initiation and subsequent adherence of the oral semaglutide therapy. We hope that this communication assists clinicians to counsel their patients in the appropriate usage of oral semaglutide.

Table 2: Semaglutide specific counseling tips: AEIOU

Ask for permission to manage Assess biomedical and psychosocial status Explore specific needs, wishes, and preferences related to medication Express the need for use of medication with proven glucose-lowering and cardiovascular benefit Identify significant point related to advantages of semaglutide, e.g. Oral administration Once-daily dosage Glycemic control Weight loss Cardiovascular benefit Introspect regarding Limitations of semaglutide, e.g. Cost Transient gastrointestinal effect Offer other options, with cost-benefit ratio Observe patient’s response to each suggestion Underscore the characteristics of oral semaglutide which can help meet the patient’s requirements Understand limitations of oral semaglutide, and suggest means of mitigation

Declaration of interest

The contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication.

Sanjay Kalra has received honoraria from Novo Nordisk, Eli Lilly, and Sanofi.

Atul Kalhan – There was no conflict of interest while this article was written, but they have received speaker fees and educational grants from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Sanofi, NAPP, Takeda.

Reviewer disclosure

A reviewer on this manuscript has disclosed that they served as the first author for PIONEER 10. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.