Integrating oral semaglutide into clinical practice in primary care: for whom, when, and how?

Figures & data

Table 1. Summary of PIONEER 1–8 study design and clinical efficacy results

	Study design				Baseline characteristics			Efficacy
Study design	Population	Comparator(s)	Number of patients per group	Study duration	Mean age	Mean diabetes duration	HbA1c	Primary endpoint	Result*	Confirmatory secondary endpoint	Result*	Conclusion
PIONEER 1 [1]	T2D uncontrolled with management only through diet and exercise	Pbo	3 mg: 175 7 mg: 175 14 mg: 175 Pbo: 178	26 weeks	55 years	3.5 years	Eligible: 7.0–9.5% Mean: 8.0%	Change in HbA1c from baseline to week 26	3 mg: –0.9%^† 7 mg: –1.2%^† 14 mg: –1.4%^† Pbo: –0.3%	Change in body weight from baseline to week 26	3 mg: –1.5 kg 7 mg: –2.3 kg 14 mg: – 3.7 kg^† Pbo: –1.4 kg	Oral semaglutide was superior to placebo in reducing HbA1c and body weight^§ at week 26 in T2D uncontrolled with management only through diet and exercise
PIONEER 2 [5]	T2D uncontrolled on metformin	Empagliflozin 25 mg once daily	14 mg: 411 Empa: 410	52 weeks	58 years	7.4 years	Eligible: 7.0–10.5% Mean: 8.1%	Change in HbA1c from baseline to week 26	14 mg: –1.3%^‡ Empa: –0.9%	Change in body weight from baseline to week 26	14 mg: –3.8 kg^¶ Empa: –3.7 kg	Oral semaglutide was superior to empagliflozin in reducing HbA1c at week 26^¶ in T2D uncontrolled on metformin
PIONEER 3 [6]	T2D uncontrolled on metformin ± SU	Sitagliptin 100 mg once daily	3 mg: 466 7 mg: 465 14 mg: 465 Sita: 467	78 weeks	58 years	8.6 years	Eligible: 7.0–10.5% Mean: 8.3%	Change in HbA1c from baseline to week 26	3 mg: –0.6%^‖ 7 mg: –1.0%^‡ 14 mg: –1.3%^‡ Sita: –0.8%	Change in body weight from baseline to week 26	3 mg: –1.2 kg^‡ 7 mg: –2.2 kg^‡ 14 mg: –3.1 kg^‡ Sita: –0.6 kg	Oral semaglutide 7 and 14 mg were superior to sitagliptin in reducing HbA1c and body weight at week 26 in T2D uncontrolled on 1–2 oral drugs
PIONEER 4 [4]	T2D uncontrolled on metformin ± SGLT2i	Liraglutide 1.8 mg once daily s.c. injection Pbo	14 mg: 285 Lira: 284 Pbo: 142	52 weeks	56 years	7.6 years	Eligible: 7.0–9.5% Mean: 8.0%	Change in HbA1c from baseline to week 26	14 mg: –1.2%^† Lira: –1.1% Pbo: –0.2%	Change in body weight from baseline to week 26	14 mg: –4.4 kg^†‡ Lira: –3.1 kg Pbo: –0.5 kg	Oral semaglutide was noninferior to liraglutide in reducing HbA1c and superior in reducing body weight at week 26, and superior to placebo for both endpoints in T2D uncontrolled on 1–2 oral drugs
PIONEER 5 [2]	Moderate renal impairment^# and T2D uncontrolled on metformin, SU or both, or insulin ± metformin	Pbo	14 mg: 163 Pbo: 161	26 weeks	70 years	14.0 years	Eligible: 7.0–9.5% Mean: 8.0%	Change in HbA1c from baseline to week 26	14 mg: –1.0%^† Pbo: –0.2%	Change in body weight from baseline to week 26	14 mg: –3.4 kg^† Pbo: –0.9 kg	Oral semaglutide was superior to placebo in reducing HbA1c and body weight at week 26 in T2D with moderate renal impairment
PIONEER 6 [8]	T2D at high CV risk^Ω	Pbo	14 mg: 1591 Pbo: 1592	Event-driven (median time in trial: 15.9 months)	66 years	14.9 years	Eligible: any Mean: 8.2%	Time to first occurrence of MACE	Occurrence of primary outcome 14 mg: 3.8% of patients Pbo: 4.8% of patients Hazard ratio: 0.79 (95% CI: 0.57, 1.11); p < 0.001 for noninferiority; p = 0.17 for superiority	N/A	N/A	Oral semaglutide was noninferior to placebo for time to first MACE and was therefore considered not to cause an excess CV risk compared with placebo
PIONEER 7 [3]	T2D uncontrolled on 1–2 of metformin, SU, SGLT2i, or TZD	Sitagliptin 100 mg once daily	Flexibly dosed^▲: 253 Sita: 251	52 weeks	57 years	8.8 years	Eligible: 7.5–9.5% Mean: 8.3%	Achievement of HbA1c <7.0% at week 52	Flexibly dosed^▲: 58% of patients^† Sita: 25% of patients	Change in body weight from baseline to week 52	Flexibly dosed^▲: –2.6 kg^† Sita: –0.7 kg	Flexibly dosed oral semaglutide was superior to sitagliptin in achieving glycemic control (HbA1c <7%) and reducing body weight at week 52 in T2D uncontrolled on 1–2 oral drugs
PIONEER 8 [7]	T2D uncontrolled on insulin ± metformin	Pbo	3 mg: 184 7 mg: 182 14 mg: 181 Pbo: 184	52 weeks	61 years	15.0 years	Eligible: 7.0–9.5% Mean: 8.2%	Change in HbA1c from baseline to week 26	3 mg: –0.6%^† 7 mg: –0.9%^† 14 mg: –1.3%^† Pbo: –0.1%	Change in body weight from baseline to week 26	3 mg: –1.4 kg^† 7 mg: –2.4 kg^† 14 mg: –3.7 kg^† Pbo: –0.4 kg	Oral semaglutide was superior to placebo in reducing HbA1c and body weight when added to insulin ± metformin

*Results for oral semaglutide at stated doses, unless specified otherwise; results reported for the treatment policy estimand (an analysis of treatment effect regardless of rescue medication use or discontinuation of the study drug); ^†p < 0.05 for estimated treatment difference (continuous endpoints) or estimated odds ratio between oral semaglutide and placebo; ^‡p < 0.05 for estimated treatment difference (continuous endpoints) or estimated odds ratio (binary endpoints) between oral semaglutide and active comparator; ^§body weight reduction superior compared with placebo for oral semaglutide 14 mg only; ^¶body weight reduction was not significantly different for oral semaglutide versus empagliflozin at week 26 for either the treatment policy estimand (an analysis of treatment effect regardless of rescue medication use or discontinuation of the study drug) or trial product estimand (an analysis of treatment effect in those remaining on-treatment without use of rescue medication); statistically significant reductions were found with oral semaglutide at week 52 for the trial product estimand (oral semaglutide: –4.7 kg; empagliflozin: –3.8 kg; p < 0.05), but not the treatment policy estimand; ^‖p < 0.05 for estimated treatment difference (continuous endpoints) or estimated odds ratio (binary endpoints) in favor of active comparator; ^#moderate renal impairment defined as estimated glomerular filtration rate of 30–59 mL/min/1.73 m² (calculated by Chronic Kidney Disease-Epidemiology Collaboration formula); ^Ωaged ≥50 years with established CV disease or chronic kidney disease, or aged ≥60 years with CV risk factors; ^▲initiated at 3 mg with doses increased (to 7 or 14 mg) or decreased (minimum: 3 mg) every 8 weeks on the basis of HbA_1c and tolerability criteria.

CI, confidence interval; CV, cardiovascular; Empa, empagliflozin; HbA_1c, glycated hemoglobin; Lira, liraglutide; MACE, major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke); N/A, not applicable; Pbo, placebo; s.c., subcutaneous; SGLT2i, sodium-glucose co-transporter-2 inhibitor; Sita, sitagliptin; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione.

Figure 1. Key considerations for the use of oral semaglutide across a spectrum of clinical scenarios in type 2 diabetes

CV, cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; MEN 2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; s.c., subcutaneous; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; T2D, type 2 diabetes.

Figure 2. The rationale for oral semaglutide early in the type 2 diabetes disease course, in a patient with inadequate glycemic control on metformin: an illustrative case study

*Options mentioned at either second or later lines of therapy (excluding insulin) within American Diabetes Association recommendations for patients receiving first-line metformin who have HbA_1c above their personal target and have a compelling need to minimize weight gain or promote weight loss [20]. BMI, body mass index; CKD, chronic kidney disease; CV, cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; s.c., subcutaneous; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione.

Panel 1. Estimand use in the PIONEER trial program

• The treatment policy estimand assessed the treatment effect regardless of whether trial participants discontinued treatment or used rescue medication [31].

• By contrast, the trial product estimand used in the PIONEER program assessed the treatment effect assuming all trial participants remained on study-drug treatment without use of rescue medication [31].

• An introduction to the concept of estimands is provided in article 2 of this supplement [27], and their use in the PIONEER program has been comprehensively reviewed by Aroda and colleagues [31].

Figure 3. The rationale for oral semaglutide at a later stage in the type 2 diabetes disease course, in a patient with inadequate glycemic control on insulin and metformin and with prior cardiovascular disease: an illustrative case study

*Based on the American Association of Clinical Endocrinologists and American College of Endocrinology management algorithm for adding/intensifying insulin [19]; ^†for example, dulaglutide, liraglutide, s.c. semaglutide, canagliflozin, dapagliflozin, or empagliflozin [9,17,18,51–53]. ADA, American Diabetes Association; BMI, body mass index; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; MI, myocardial infarction; s.c., subcutaneous; SGLT2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes.

Panel 2. Exploring the risks of thyroid C-cell tumors with GLP-1RAs

What do we know about the risk?

• There are four main types of thyroid cancer: the more common papillary and follicular forms (differentiated thyroid cancers), and the rare medullary and anaplastic forms (poorly differentiated thyroid cancers) [60–62].

• Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid C cells [61–63] and accounts for approximately 2% of thyroid cancer cases in the US [60].

• In studies in rodents, several GLP-1RAs, including semaglutide, have been found to cause thyroid C-cell tumors; however, it is important to note that the relevance of these observations for humans is unknown [9,13,14,17,18].

• It is therefore not recommended to use oral semaglutide in patients with a personal or family history of MTC. MTC can run in families, sometimes in association with multiple endocrine neoplasia syndrome type 2 (MEN 2) [63], and consequently, it is also recommended to avoid use of GLP-1RAs (including oral semaglutide) in patients with MEN 2 [9].

How often have MTCs been reported with GLP-1RAs?

• Prescribing information mentions one report of MTC with dulaglutide (plus an additional case of C-cell hyperplasia with elevated calcitonin levels) and post-marketing cases of MTC with liraglutide, but there are not enough data to evaluate any causal relationship between MTC incidence and GLP-1RA treatment [9,13,14,17,18].

• More generally, meta-analyses exploring the incidence of cancer in trials of GLP-1RAs did not identify an increased risk of cancer, including for thyroid cancers, compared with placebo or other glucose-lowering therapies [64–66].

Figure 4. Key communication points for counseling patients suitable for initiation of oral semaglutide [9,59,76]

AE, adverse event; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist.

Panel 3. An illustrative clinical discussion exploring administration recommendations for oral semaglutide

Dr A: • I’m planning to start one of my patients on oral semaglutide – how should I recommend that they take it? Dr B: • As food and other tablets can impact the absorption of oral semaglutide [72,73], the patient should be instructed to take oral semaglutide on an empty stomach after they wake up [9]. • The patient should swallow the tablet whole (not split, crushed, or chewed) with a sip of plain water (up to 4 fl oz/120 mL) and then wait at least 30 minutes before eating, drinking beverages, or taking other oral medications [9]. • The prescribing information suggests that eating 30–60 minutes after taking oral semaglutide helps it work best [9]. Dr A: • They’re taking quite a few other drugs – is that a problem? Dr B: • In general, patients should be instructed to take oral semaglutide on an empty stomach after they wake up and then to wait at least 30 minutes before taking any other oral medications [9]. • If they’re taking insulin or a sulfonylurea (or another insulin secretagogue), you should consider reducing the dose when initiating oral semaglutide to lower the risk of hypoglycemia [9], like you would when starting other agents like SGLT2 inhibitors [19,51–53]. • If they’re on thyroid hormone replacement with levothyroxine and currently take it in the morning, they may need to change how they take levothyroxine, as taking oral semaglutide and levothyroxine together increases thyroxine exposure [9]. It’s therefore suggested to follow the administration recommendations for oral semaglutide [9]. Taking levothyroxine at bedtime (at least 3 hours after the last meal of the day) could be considered instead of in the morning [74]. As you would do in such patients, close monitoring of thyroxine parameters is recommended, in line with thyroid hormone replacement guidelines [74]. • In addition, if they’re taking any other oral medication with a narrow therapeutic index or that requires clinical monitoring, you may need to consider increasing the frequency of monitoring [9].

See Figure 4 for key communication points for counseling patients.

Panel 4. Key safety outcomes across the global PIONEER trial program [1–7,9]

• The most frequently reported AEs in patients treated with oral semaglutide were GI disorders – namely nausea, vomiting, and diarrhea. • These AEs were generally mild to moderate in severity and transient, typically occurring during the dose escalation period. • The incidence of severe or blood glucose-confirmed symptomatic hypoglycemia was generally low in patients treated with oral semaglutide; cases were most commonly reported in patients who were also receiving a sulfonylurea or insulin. • Across the PIONEER program, the incidence of diabetic retinopathy-related AEs was similar for patients treated with oral semaglutide, placebo, or the active comparators; most cases were diagnosed during routine eye examinations and did not require active treatment. • Reports of external independent adjudication committee-confirmed acute pancreatitis and acute kidney injury were few in number, and rates were similar between oral semaglutide and comparators.

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