Oral semaglutide in type 2 diabetes

Journal Pre-proof Oral semaglutide in type 2 diabetes

Sarah L. Anderson, Trevor R. Beutel, Jennifer M. Trujillo PII:

S1056-8727(19)31158-4

DOI:

https://doi.org/10.1016/j.jdiacomp.2019.107520

Reference:

JDC 107520

To appear in:

Journal of Diabetes and Its Complications

Received date:

16 October 2019

Revised date:

12 November 2019

Accepted date:

30 December 2019

Please cite this article as: S.L. Anderson, T.R. Beutel and J.M. Trujillo, Oral semaglutide in type 2 diabetes, Journal of Diabetes and Its Complications(2020), https://doi.org/10.1016/ j.jdiacomp.2019.107520

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© 2020 Published by Elsevier.

Journal Pre-proof Oral Semaglutide in Type 2 Diabetes Sarah L. Anderson,a Trevor R. Beutel,b Jennifer M. Trujilloc

a. Associate Professor, University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences, Department of Clinical Pharmacy, 12850 E. Montview Blvd., Aurora, CO 80045. 303-724-5926 (ph). 303-724-2627 (fax).

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[email protected] b. PharmD Student; University of Colorado Skaggs School of Pharmacy & Pharmaceutical

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Sciences, 12850 E. Montview Blvd., Aurora, CO 80045. 732-996-9929 (ph).

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[email protected]

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c. Professor, University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences, Department of Clinical Pharmacy, 12850 E. Montview Blvd., Aurora, CO

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(corresponding author)

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80045. 303-724-2624 (ph). 303-724-2627 (fax). [email protected]

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diabetes

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Key words: oral semaglutide; Rybelsus; glucagon-like peptide-1 receptor agonist; type 2

Funding: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Journal Pre-proof Abstract Background: Previously, the only available glucagon-like peptide-1 receptor agonists (GLP-1 RA) were injectable. Approval of oral semaglutide (Rybelsus®) represents the first orally available GLP-1 RA. Objective: To review the literature and describe pharmacologic, pharmacokinetic, and pharmacodynamics properties; clinical safety; and efficacy of oral semaglutide, a newly

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approved oral GLP-1 RA. Methods: A MEDLINE (1995-October 2019) and ClinicalTrials.gov search was conducted using

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the terms oral semaglutide, semaglutide, PIONEER, and a combination of those terms.

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Reference citations from publications identified were also reviewed. All English-language

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studies, including abstracts, evaluating oral semaglutide use in humans were included in this review.

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Conclusions: The approval of oral semaglutide (Rybelsus®) represents a paradigm shift in the

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management of T2D as this is the first FDA-approved oral GLP-1 RA. Oral semaglutide may be an attractive option for patients with T2D who require improved glycemic control, would like to

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lose weight, and who are not interested in injectable therapy. However, the lack of positive

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cardiovascular (CV) and renal data are significant limitations to its use.

Journal Pre-proof Introduction The broad treatment armamentarium for type 2 diabetes (T2D) allows for a patient-centered approach to achieving and maintaining glycemic control. Following metformin and lifestyle modifications, there are a variety of second-line treatment options available [ADA 2019]. Selection of a second-line agent is based on a combination of patient-specific factors, including presence of comorbid conditions, weight, hypoglycemia risk, cost, and patient preference.1

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Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are one such treatment option that have a wealth of data supporting their glucose-lowering efficacy, favorable safety profile, and in the

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case of some agents, improvement in CV outcomes.2-4

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A limitation to the use of currently available GLP-1 RAs is that they are administered via subcutaneous injection in order to avoid enzymatic and pH degradation of the peptide in the

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gastrointestinal (GI) tract. Patients with T2D often have difficulty with adherence to and persistence with injectable medications, with “injection concerns” being one of the most

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frequently cited barriers.5-7 In order to overcome this barrier, an oral formulation of the GLP-1

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RA semaglutide has been developed through co-formulation with an absorption enhancer. Oral

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semaglutide was studied in the PIONEER clinical trial program and was recently approved by the Food and Drug Administration (FDA) under the brand name Rybelsus® for the treatment of adults with T2D (Figure 1).8 Oral semaglutide is available in 3mg (starting dose), 7mg, and 14mg tablets. This review discusses the pharmacology, efficacy, safety, and place in therapy of the first oral GLP-1 RA, oral semaglutide.

Data Sources A MEDLINE search (1995-October 2019) was conducted using the search terms oral semaglutide, semaglutide, PIONEER, and a combination of those terms. Review of the references listed in the articles identified was also performed. The oral semaglutide prescribing

Journal Pre-proof information was reviewed, as well as abstracts from scientific meetings and ongoing clinical trial data.

Pharmacology Semaglutide is a 31-amino acid peptide that mimics native GLP-1 with two key structural modifications: substitution of alanine at position 8 with α-aminoisobutyric acid and addition of a

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spacer to conjugate the C18 fatty diacid to the position 26 lysine. These modifications allow for resistance of drug degradation by dipeptidyl peptidase-4 (DPP-4) and reduced renal clearance

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of the drug respectively, resulting in prolonged plasma half-life.9,10 Successful oral delivery of

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native GLP-1 co-formulated with the absorption enhancer SNAC (sodium N ‐[8‐(2‐

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hydroxybenzoyl)amino] caprylate) has been previously demonstrated. SNAC is a hydrophobic molecule that noncovalently binds to GLP-1 and other related peptides, resulting in increased

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lipophilicity of the peptide molecule(s). Oral administration of GLP-1 co-formulated with SNAC

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results in increased GLP-1 transport across intestinal epithelium. The noncovalent bonds between SNAC and GLP-1 are readily broken upon exposure to the bloodstream, allowing for

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circulation of unbound GLP-1.11

Semaglutide is a GLP-1 RA that decreases blood glucose via the primary mechanisms of increasing insulin secretion and decreasing glucagon secretion, both in a glucose-dependent manner.12 Gastric emptying is delayed in the early post-prandial phase. Semaglutide decreases both fasting and post-prandial blood glucose levels as well as body weight.

Pharmacokinetics and Pharmacodynamics Oral semaglutide undergoes gastric absorption, which is different from all other available GLP-1 RAs.13 Gastric absorption is also different from most other oral medications, which are more commonly absorbed in the intestines. Oral administration of semaglutide in the fasted state with

Journal Pre-proof up to 120ml of water followed by a 30-minute post-dosing fast results in maximal systemic absorption.14 This is because SNAC protects semaglutide from pH-dependent degradation and food consumption increases the gastric pH.13 Oral semaglutide is less bioavailable and has more absorption variability from patient-to-patient than injectable semaglutide, which is why a higher dose is needed for the oral formulation.15 Research has shown safety and tolerability of oral semaglutide dosed once daily for ten weeks in both healthy volunteers and patients with

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T2D.16 The use of oral semaglutide has been studied in patients with varying degrees of hepatic or renal impairment. There were no differences in area under the curve (AUC), maximum

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concentration (Cmax), or half-life (t1/2) in patients with mild, moderate, or severe hepatic

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impairment as compared to patients with normal hepatic function; therefore, no hepatic dose

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adjustments are recommended.17 In patients with mild, moderate, or severe renal impairment and those with end-stage renal disease on hemodialysis (ESRD-HD), there was no significant

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difference in AUC or t1/2 as compared to patients with normal renal function.15 Researchers

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concluded there were no clinically relevant differences in pharmacokinetics (PK) based on

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degree of renal impairment; therefore, no renal dosing adjustments are required.

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Several studies examined the presence and severity of drug-drug interactions with oral semaglutide and other commonly prescribed medications. No clinically relevant drug-drug interactions have been observed with oral semaglutide co-administered with omeprazole, lisinopril, warfarin, metformin, or digoxin.18,19 Despite the lack of data regarding drug-drug interactions, the prescribing information recommends waiting 30 minutes before taking other medications after the administration of oral semaglutide to ensure optimal semaglutide absorption. Because oral semaglutide can delay gastric emptying, this has the potential to affect absorption of other oral medications.

Dose Ranging Studies

Journal Pre-proof Safety and tolerability of single oral semaglutide doses ranging from 2mg to 20mg co-formulated with SNAC were demonstrated in a phase II trial.20 The trial analyzed the effect of varying doses of SNAC when co-formulated with fixed doses of oral semaglutide. Two pairs of co-formulations were analyzed: 5mg oral semaglutide/300mg SNAC vs. 5mg oral semaglutide/150mg SNAC and 10mg oral semaglutide/300mg SNAC vs. 10mg oral semaglutide/600 mg SNAC. The formulation with 300mg SNAC resulted in significantly greater semaglutide plasma

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concentrations than the comparator co-formulation in both analyses. A linear relationship was observed in semaglutide plasma concentrations between oral semaglutide doses of 2mg, 5mg,

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and 10mg when co-formulated with 300mg SNAC. The authors concluded that 300mg SNAC is

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the optimal dosage for co-formulation with oral semaglutide.

Dose ranges and escalations of oral semaglutide for the treatment of T2D were studied in a

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phase II randomized controlled trial.21 Once daily oral semaglutide doses of 2.5mg, 5mg, 10mg,

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20mg, and 40mg were studied and all doses showed significantly greater glycosylated hemoglobin A1C (A1C) reduction than placebo and were dose-dependent. There was no

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statistically significant difference in A1C reduction observed in the 20mg and 40mg oral

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semaglutide groups compared to the 1mg injectable semaglutide once weekly group. The most common adverse events observed with oral semaglutide were mild to moderate nausea and less frequently, vomiting and diarrhea. These events occurred at similar rates in both the oral and injectable semaglutide arms. Serious adverse events were rare with no differences in event rates between groups. These data suggest that once daily doses of oral semaglutide ranging from 2.5mg to 40mg are well tolerated and efficacious for the treatment of T2D. Oral semaglutide doses of 3mg, 7mg, and 14mg were studied in Phase III clinical trials.

Efficacy: Summary of Phase III Clinical Trials

Journal Pre-proof The PIONEER trial program, evaluating the efficacy and safety of oral semaglutide, is one of the first clinical trial programs in T2D to use estimands. This is due to the US FDA recommending against the use of last observation carried forward (LOCF) because it is a flawed approach for handling missing data.22 At its simplest, an estimand is that which is being estimated. In a clinical trial, estimands may be included in order to align the trial objective, design, conduct, and data analysis. Most clinical trials report statistical endpoints that incorporate the population of

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interest (e.g., adults with T2D), the endpoint of interest (e.g., A1C at 52 weeks), and a population level summary (e.g., mean difference between treatment group and placebo).

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However, most clinical trials do not have a robust way to report out intercurrent events, such as

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use of a rescue medication and premature study discontinuation.

The PIONEER trial program used two estimands – a “treatment policy estimand” and a “trial

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product estimand.” The treatment policy estimand aimed to describe the treatment effect in

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patients with T2D regardless of trial product (oral semaglutide) discontinuation or use of rescue medication while the trial product estimand aimed to describe the treatment effect in patients

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with T2D if all patients had continued use of the trial product (oral semaglutide) and did not use rescue medication.23 The treatment policy estimand is the more conservative of the two given

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that it focuses on an intent-to-treat population and includes all patients’ data.

For purposes of this manuscript, we have reported out both the treatment policy and trial product estimand data in Table 1, which focuses on results from the primary endpoint timeframe only and provides actual change from baseline in each group. When describing endpoints in the text we have focused on the treatment policy estimand, placebo-adjusted results and includes information on multiple time points if applicable to the study.

Placebo Comparators: Use as monotherapy

Journal Pre-proof In the PIONEER 1 study, 703 patients with T2D who had not achieved their A1C goal despite diet and exercise were randomized to receive oral semaglutide or placebo.24 The primary endpoint was change in A1C from baseline to week 26 and a secondary endpoint was change in body weight during the same timeframe. At baseline, the mean A1C was 8.0%, mean age was 55 years, and 50.8% of patients were male. Patients were randomized 1:1:1:1 to oral semaglutide 3mg, 7mg, 14mg, or placebo. Rescue medication was prescribed at the

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investigators’ discretion if fasting plasma glucose (FPG) was > 240 mg/dl from weeks 8 through 13 or > 200 mg/dl from week 14 onwards. All doses of oral semaglutide resulted in reductions in

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A1C. The placebo-adjusted treatment differences in A1C at week 26 were: -0.6% (-0.8 to -0.4)

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for 3mg, -0.9% (-1.1 to -0.6) for 7mg, and -1.1% (-1.3 to -0.9) for 14mg (all p < 0.001). The

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14mg dose of oral semaglutide provided superior reductions in body weight compared to placebo and both the 7mg and 14mg provided statistically significant weight reduction. The

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placebo-adjusted treatment differences in body weight at week 26 were: -0.1 kg (-0.9 to 0.8) for

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3mg (p=0.87), -0.9 kg (-1.9 to 0.1) for 7mg (p=0.09), and -2.3 kg (-3.1 to -1.5) for 14 mg (p < 0.001). The authors concluded that oral semaglutide, used as monotherapy in patients with

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T2D, was more effective than placebo and commented that the effects observed in this study

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were similar to those seen with other GLP-1 RA monotherapy, placebo-comparator studies.

Placebo Comparators: Use as combination therapy PIONEER 8 was a randomized trial of 731 patients with T2D uncontrolled on basal insulin with or without metformin who were assigned 1:1:1:1 to received oral semaglutide 3mg, 7mg, or 14mg or placebo for 52 weeks.25 Randomization was stratified by country of origin (Japanese and non-Japanese). Compared to other PIONEER studies, this trial enrolled older patients (mean age 61 years) who had had diabetes for a mean of 15 years. Patients’ insulin dose was pre-emptively reduced by 20% and maintained until week 8 unless an increase was necessary. Insulin dosing was able to be altered during weeks 8 to 26 without exceeding the pre-

Journal Pre-proof randomization dose. For the second 26 weeks, insulin dose adjustments were freely allowed. At weeks 26 and 52 oral semaglutide demonstrated significantly greater decreases in A1C than placebo (estimated treatment difference [ETD] -0.5 to -1.2% at week 26 and -0.4 to -0.9% at week 52; p < 0.001 for all oral semaglutide vs. placebo differences). Similarly, weight loss with oral semaglutide was statistically significantly greater than placebo at weeks 26 (ETD -0.9 to 3.3 kg; p < 0.05 for all oral semaglutide vs. placebo differences) and 52 (ETD -1.3 to -4.3 kg

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compared to placebo; p < 0.05 for all oral semaglutide vs. placebo comparisons). At 52 weeks, all groups of oral semaglutide had significantly lower doses of basal insulin compared to

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placebo (-8 units for 3mg [p < 0.05], -16 units for 7mg [p< 0.001], and -17 units for 14mg

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[p<0.001]). There was no difference in rates of hypoglycemia between oral semaglutide and

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placebo. The most frequent adverse effect related to oral semaglutide was nausea (11.4 to 23.2% vs. 7.1% with placebo). The authors concluded that oral semaglutide was an effective

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add-on to insulin ± metformin and has a side effect profile consistent with injectable GLP-1 RAs.

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Active Comparators – Sodium Glucose Co-transporter 2 (SGLT-2) inhibitors

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The PIONEER 2 study was a 52-week, open label trial in which 821 patients with T2D were randomized to receive semaglutide 14mg or empagliflozin 25mg, on a background of metformin

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therapy.26 At baseline, the mean age was 57 years, mean A1C was 8.1%. At week 26, the mean A1C reduction was -1.3% with oral semaglutide compared with -0.9% with empagliflozin. These differences were statistically significant for demonstrating superiority of semaglutide over empagliflozin and were maintained at week 52. Body weight loss was similar between groups; at week 52, oral semaglutide-treated patients had lost a mean of 3.8 kg compared with 3.7 kg for the empagliflozin group (p=0.05). The authors concluded that oral semaglutide 14mg produced superior A1C lowering compared to empagliflozin 25mg at weeks 26 and 52. Body weight reduction was not statistically different at week 26 but oral semaglutide demonstrated superior weight reduction at week 52 by trial product estimand.

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Active Comparators – Dipeptidyl Peptidase 4 (DPP-4) inhibitors Oral semaglutide was compared with sitagliptin in 1,864 patients with T2D receiving background therapy with metformin, with or without a sulfonylurea, in the PIONEER 3 study.27 At baseline, the mean age was 58 years, mean A1C was 8.3%, and 47.2% of patients were female. Patients were randomized 1:1:1:1 to receive oral semaglutide 3mg, 7mg, or 14mg or sitagliptin 100mg

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daily for 78 weeks. All patients randomized to oral semaglutide started at a dose of 3mg and the dose was escalated every 4 weeks until the randomized dosage was achieved. Results were

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reported out at week 26. The changes in A1C at week 26 were -0.6%, -1.0%, and -1.3% for oral

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semaglutide 3 mg, 7mg, and 14mg, respectively, and -0.8% for sitagliptin 100mg. The 7mg and

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14mg doses of oral semaglutide were superior to sitagliptin with regard to A1C reduction (p < 0.001 for both). Mean changes in body weight at week 26 were -1.2 kg, -2.2 kg, and -3.1 kg for

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oral semaglutide 3 mg, 7mg, and 14mg, respectively, and -0.6kg for sitagliptin 100mg. Again,

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the 7mg and 14mg doses of oral semaglutide were superior to sitagliptin with regard to weight reduction (p < 0.001 for both). At week 78, the A1C reductions continued to be significantly

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greater with the oral semaglutide 7mg (trial product estimand only) and 14mg doses compared

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with sitagliptin. For all doses of oral semaglutide, weight reductions were superior to sitagliptin by both estimands. Study authors concluded that oral semaglutide 7mg and 14mg doses were superior in efficacy compared to sitagliptin for both A1C and body weight reduction.

The PIONEER 7 trial also compared oral semaglutide with sitagliptin, but with a flexible dosing strategy.28 Over 500 patients were randomized to flexibly-dosed oral semaglutide or sitagliptin 100mg daily. Oral semaglutide was started at 3mg daily and the dose was adjusted at week 8 and every 8 weeks after based on A1C measured by point-of-care device and/or based on tolerability of the study drug. The mean age at baseline was 57.4 years, mean A1C was 8.3%, and 57% of patients were male. At week 8, 73% of patients in the oral semaglutide group were

Journal Pre-proof dose-increased to 7mg. By week 52, 9% of patients in the oral semaglutide group were receiving 3mg, 30% were receiving 7mg, and 59% were receiving 14mg. Twice as many patients in the sitagliptin group received additional glucose-lowering drugs compared to patients in the oral semaglutide group. Oral semaglutide resulted in significantly greater decreases in A1C than sitagliptin (ETD -0.5%; 95% CI -0.7 to -0.4; p < 0.0001). At week 52, 58% of patients in the oral semaglutide group achieved an A1C of < 7% compared to 25% in the sitagliptin

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group (p < 0.0001). Oral semaglutide also resulted in significantly greater weight loss than sitagliptin (ETD -1.9 kg; 95% CI -2.6 to -1.2; p < 0.0001). The authors concluded that flexibly-

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dosed oral semaglutide was superior to sitagliptin with respect to A1C and body weight

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reductions and achieved these outcomes despite having fewer add-on medications for glucose

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Active Comparators – injectable GLP-1 RA

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lowering.

Oral semaglutide was compared to liraglutide in a 52-week clinical trial.29 Patients with T2D

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were randomly assigned in 2:2:1 fashion to receive oral semaglutide (dose-escalated to 14mg),

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liraglutide (dose-escalated to 1.8mg), or placebo. At baseline, the mean age was 56 years, mean A1C was 8.0%, and 48% of patients were female. At week 26, oral semaglutide

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demonstrated significantly greater decreases in A1C compared to both liraglutide (ETD -0.2%; 95% CI -0.3 to -0.1; p=0.0056) and placebo (ETD -1.2%; 95% CI -1.4 to -1.0; p < 0.0001), which was also seen at 52 weeks (ETD for liraglutide -0.3%; 95% CI -0.5 to -0.1; p=0.0002 and ETD for placebo -1.0%; 95% CI -1.2 to -0.8; p < 0.0001). Similarly, weight loss with oral semaglutide was statistically significantly greater than both liraglutide and placebo at weeks 26 (ETD for liraglutide -1.2 kg; p=0.0003 and ETD for placebo -3.8 kg; p < 0.0001) and 52 (ETD for liraglutide -1.3 kg; p=0.0019 and ETD for placebo -3.3 kg; p < 0.0001). Oral semaglutide was non-inferior to liraglutide and superior to placebo in decreasing A1C. Oral semaglutide was superior to both liraglutide and placebo in decreasing body weight. The authors concluded that

Journal Pre-proof oral semaglutide offers a comparable option to an injectable GLP-1 RA in patients who are reluctant to initiate or intensify injectable GLP-1 RA therapy.

Other PIONEER trials There are 10 trials in the PIONEER trial series; PIONEER 9 and 10 have not yet been

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published. However, there are preliminary results available for each.

PIONEER 9 compared the use of oral semaglutide 3mg, 7mg, and 14mg vs. liraglutide 0.9mg

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(maximum allowable dose in Japan) and vs. placebo in 243 Japanese adults with T2D.30 All

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doses of oral semaglutide resulted in a statistically significant reduction from baseline A1C at 26

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weeks compared to placebo. Oral semaglutide 14mg achieved a statistically significant reduction in A1C compared to liraglutide 0.9mg (-1.7% vs. -1.4%) at week 26. At 52 weeks, all

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doses of oral semaglutide maintained a statistically significant reduction in A1C, but the 14mg

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dose was no longer superior to liraglutide. Also at 52 weeks, use of oral semaglutide 14mg resulted in statistically significantly greater weight loss (-2.8 kg) compared to either placebo (-

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1.0 kg) or liraglutide (+0.4 kg).

PIONEER 10 was a randomized, open label trial in 44 Japanese patients with uncontrolled T2D on one oral antidiabetic agent.31 Patients were randomized to oral semaglutide 3mg, 7mg, or 14mg or dulaglutide 0.75mg. Oral semaglutide 14mg had a statistically significant reduction in A1C compared to dulaglutide at 52 weeks (-1.8% vs. -1.3%). Similarly, weight loss with oral semaglutide 14mg was statistically significant compared to dulaglutide at 52 weeks (-1.9 kg vs. 1.1 kg).

Efficacy in Special Populations

Journal Pre-proof There is one placebo-controlled, active comparator study evaluating oral semaglutide in patients with T2D and renal dysfunction. The PIONEER 5 study compared oral semaglutide to placebo in 324 patients with T2D who had been receiving a stable dose of metformin or sulfonylurea or both, or basal insulin with or without metformin use.32 Patients also had to have an estimated glomerular filtration rate (eGFR) of 30 to 59 ml/min/1.73m2. At baseline, the mean A1C was 8.0%, mean age was 70 years, mean eGFR was 48 ml/min/1.73m2, and 52% of patients were

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female. Patients were randomized 1:1 to oral semaglutide or placebo in addition to their current background therapy. The dose of oral semaglutide was initiated at 3mg, then increased to 7mg

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at 4 weeks and further increased to 14mg at 8 weeks. Oral semaglutide was superior to placebo

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in decreasing A1C and body weight over 26 weeks. At week 26, the mean change in A1C from

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baseline was -1.0% for oral semaglutide and -0.2% for placebo (ETD -0.8%; 95% CI -1.0 to -0.6; p < 0.0001). The mean change in body weight at week 26 was -3.4 kg for oral semaglutide and -

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0.9 kg for placebo (ETD -2.5 kg; 95% CI -3.2 to -1.8; p < 0.0001). Changes in A1C and body

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weight were similar to the results of PIONEER 1, demonstrating consistent results as monotherapy across a range of renal function. The authors concluded that these results are

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important in demonstrating that oral semaglutide is a safe option when other oral agents (e.g.,

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metformin) are not an option based on the patient’s renal function.

Key Safety Considerations General

The primary adverse effect reported in the PIONEER clinical trial series were GI related.24,26-29 Nausea in the oral semaglutide groups was the most frequently reported GI adverse event, at a rate of approximately 5 to 20% within the trial series across all doses of oral semaglutide studied. 24,26-29 The incidence of nausea appears to be dose-related. The PIONEER 7 trial allowed for a flexible oral semaglutide dosing protocol, but this did not mitigate the incidence of nausea (21% incidence).28 A recent systematic review and meta-analysis of oral semaglutide

Journal Pre-proof trials confirmed that the incidence of nausea, vomiting, and diarrhea were increased with oral semaglutide compared to placebo and were dose-related.33 Importantly, there were no differences in the incidence of hypoglycemia, renal adverse effects, or pancreatitis between oral semaglutide and placebo or oral semaglutide and active comparator (Table 2).

As with injectable GLP-1 RAs, oral semaglutide carries a black box warning stating that it should

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not be used in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2). Oral semaglutide should not be used in

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patients with a history of pancreatitis and if signs and symptoms of pancreatitis arise while on

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treatment, oral semaglutide should be discontinued. Oral semaglutide should not be used in

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pregnant women. Females who are contemplating pregnancy should discontinue oral

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semaglutide 2 months prior to attempting conception.8

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Special Populations

Similar to the other PIONEER trials, the main adverse effect noted by patients enrolled in

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PIONEER 5 (which evaluated oral semaglutide in patients with T2D and renal dysfunction) was

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nausea, at a rate of 19% for those who received oral semaglutide.32 The primary reason for study discontinuation in both the oral semaglutide and placebo groups was GI disorders (12% and 3%, respectively). Renal function remained constant throughout the study in both CKD patient subgroups from week 31 follow-up to baseline. The authors noted the overall safety profile within this population was consistent with the safety profile of injectable GLP-1 RAs.

Cardiovascular Outcomes Trial The cardiovascular (CV) safety of oral semaglutide in high CV risk patients was analyzed in the PIONEER 6 study.34 The primary outcome was the first occurrence of a major adverse cardiovascular event (MACE; death from CV causes, nonfatal myocardial infarction [MI], or

Journal Pre-proof nonfatal stroke). Patients were eligible for inclusion if they were determined to be at high CV risk, which was defined as age ≥50 years with established CV disease (CVD) or CKD, or age ≥60 years with CV risk factors, which mirrored SUSTAIN-6 inclusion criteria.2,34 Because injectable semaglutide was associated with a higher risk of diabetic retinopathy in SUSTAIN-6, patients with proliferative retinopathy or maculopathy requiring active treatment were excluded from PIONEER 6.2,34 A total of 3183 patients were randomized in a 1:1 ratio to receive either

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once daily oral semaglutide (n=1591) dose-escalated to target dose 14mg, or once daily oral placebo (n=1592). The trial was prespecified to continue until at least 122 primary outcome

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events occurred. Median time in the trial was 15.9 months, which was shorter than previous

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cardiovascular outcomes trials (CVOTs) for other antihyperglycemic agents, including the ELIXA

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(25 months), LEADER (45.6 months), SUSTAIN-6 (25.2 months), EXSCEL (38.4 months), and EMPA-REG OUTCOME (37.2 months) trials.2,3,35-37 The trial was completed by 1347 of 1591

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patients (84.7%) in the oral semaglutide group and 1435 of 1592 patients (90.1%) in the

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placebo group. More patients in the oral semaglutide group (11.6%) discontinued treatment than the placebo group (6.5%) due to adverse events, which was driven by the increased frequency

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of GI events in the oral semaglutide group.34

The primary MACE outcome occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 patients (4.8%) in the placebo group (HR, 0.79; 95% CI, 0.57 to 1.11; P<0.001 for non-inferiority). The reduction in the primary composite MACE outcome observed in the oral semaglutide group was largely driven by the 51% reduction in CV mortality. However, the 21% reduction in the primary endpoint with oral semaglutide was non-statistically significant. The trial investigators concluded that oral semaglutide was non-inferior to placebo.34

Secondary outcomes included CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalization, heart failure (HF) requiring hospitalization, all-cause mortality, and composite

Journal Pre-proof outcomes of these secondary events. There was a significant decrease in CV deaths in the oral semaglutide group (15 of 1591 patients, 0.9%) compared with the placebo group (30 of 1592 patients, 1.9%; HR 0.49; 95% CI 0.27 – 0.92). All-cause mortality occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 patients (2.8%) in the placebo group (HR, 0.51; 95% CI, 0.31 to 0.84). All-cause mortality was largely driven by CV mortality in

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both groups.34

In the SUSTAIN-6 trial, there were significantly fewer CV events for patients at high CV risk

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treated with injectable semaglutide compared with placebo. SUSTAIN-6 demonstrated

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superiority of injectable semaglutide in comparison to placebo for the same composite MACE

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outcome described in the PIONEER 6 trial (HR 0.74; 95% CI, 0.58 – 0.95). Secondary outcome analyses showed no difference between the two groups for CV death and all-cause mortality.2

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Compared to PIONEER 6, SUSTAIN-6 was longer in duration (104 weeks compared to

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approximately 64 weeks) and had more CV events occur. PIONEER 6 included more patients with established CVD (84.7%) compared to SUSTAIN-6 (80.3%). SUSTAIN-6 showed a

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statistically significant decrease in nonfatal stroke (HR 0.61; 95% CI, 0.38-0.99; p=0.04)

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whereas PIONEER 6 showed a significant reduction in CV deaths (Table 3).2,34 It is possible that while oral and injectable semaglutide demonstrate similar glycemic effects, their effects on the CV system may be different.

PIONEER 6 was powered to show non-inferiority of oral semaglutide compared to placebo in the primary composite MACE outcome. Non-inferiority was demonstrated; however, further randomized controlled trials are needed to determine if oral semaglutide is superior to placebo and if there are differences in the incidence of MACE with the use of oral versus injectable semaglutide. PIONEER 6 was the first trial to demonstrate CV safety of an oral GLP-1 RA with no increase in incidence of diabetic retinopathy during the trial.

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Place in Therapy The American Diabetes Association (ADA) Standards of Medical Care in Diabetes recommend that in the absence of contraindications, metformin is the preferred initial pharmacologic option for the treatment of T2D.1 The choice of which agent to add second depends on patient-specific factors. The guidelines currently advocate for the use of GLP-1 RAs that have demonstrated CV

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benefit in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) and the use of GLP-1 RAs that have demonstrated reduction in CKD progression, CV events, or

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both patients with T2D and CKD. Lastly, GLP-1 RAs are recommended in patients who desire

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weight loss, an agent with a low risk of hypoglycemia, and who need greater glucose lowering

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with an injectable agent.1 It is unclear, however, how the ADA will approach recommendations regarding oral semaglutide. The PIONEER 6 trial demonstrated non-inferior CV safety of oral

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semaglutide compared to placebo, but not superiority, in patients with T2D and CVD. This

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makes oral semaglutide less favorable than other GLP-1 RAs that have demonstrated superiority in CV risk reduction in similar patients. The Heart Disease Study of Semaglutide in

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Patients with T2D (SOUL) is still underway and should provide additional insight into the role of

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oral semaglutide in patients with T2D and heart disease.38 The PIONEER 5 trial demonstrated efficacy and safety of oral semaglutide in patients with T2D and moderate renal impairment, but not delay of CKD progression as has been demonstrated with some sodium glucose cotransporter-2 (SGLT2) inhibitors.32,39

Cost-effectiveness analyses of oral semaglutide have demonstrated that the 14mg dose is more cost effective than its comparators in the PIONEER clinical trial series in terms of cost-perpatient achieving glycemic treatment targets.40-41 The cost analysis by Hunt et al. demonstrated that based on data from PIONEER 2, 3, and 4, oral semaglutide 14mg was more cost-effective than empagliflozin, sitagliptin, and liraglutide (including daily needle cost) and had a lower

Journal Pre-proof number needed to treat (NNT) vs. all comparators in order to get a patient to their glycemic target.40 The cost analysis by Abramson et al. showed that even though the raw materials to produce oral semaglutide compared to injectable semaglutide cost more, the cost per qualityadjusted life years (QALYs) gained from an oral formulation was less those from the injectable ($85,000 per QALY for oral semaglutide vs. $110,000 per QALY for injectable semaglutide). 41 A caveat to these data is that these studies were conducted before the FDA approval of oral

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semaglutide, so future cost analyses will need to account for the actual market price of oral

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semaglutide.

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The likely place in therapy for oral semaglutide is in patients with uncontrolled T2D despite

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optimally-dosed metformin who require additional glucose lowering, would like to achieve weight loss, would like to avoid hypoglycemia, do not wish to use an injectable agent and are able to

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adhere to the oral administration instructions. Alternatively, oral semaglutide is an attractive

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option for patients with T2D whose renal function precludes use of metformin or SGLT2 inhibitors. However, oral semaglutide has not yet demonstrated benefit in preventing CKD

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progression like other GLP-1 RAs have. Use of the 14mg dose has demonstrated the ability to

tolerated.

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lower A1C > 1% and reduce weight by > 3 kg and should be the target dose to achieve, if

In patients treated with injectable semaglutide who are switching to oral semaglutide, this is accomplished by switching from the injectable semaglutide 0.5mg once weekly injection to oral semaglutide 7mg or 14mg. Patients can start oral semaglutide up to 7 days after their last injection. There is no oral semaglutide dose equivalent to injectable semaglutide 1mg once weekly and as such, no guidance on dose conversions. If a patient treated with 14mg of oral semaglutide is switching to injectable semaglutide, the patient can start 0.5mg once weekly the day after their last oral semaglutide dose.8

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Conclusions The approval of oral semaglutide (Rybelsus®) represents a paradigm shift in the management of T2D as this is the first FDA-approved oral GLP-1 RA. Oral semaglutide may be an attractive option for patients with T2D who require improved glycemic control, would like to lose weight, and who are not interested in injectable (or intensive injectable) therapy. While it is a huge

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benefit to have an oral alternative to injectable GLP-1 RAs, the lack of positive CV and renal

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data are significant limitations to its use.

Journal Pre-proof References 1. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S103-S123.

2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients

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with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.

3. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes

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in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.

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4. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-

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blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519-1529.

5. Cooke CE, Lee HY, Tong YP, Haines ST. Persistence with injectable antidiabetic agents in

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2010;26:231–238.

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members with type 2 diabetes in a commercial managed care organization. Curr Med Res Opin.

6. Spain CV, Wright JJ, Hahn RM, Wivel A, Martin AA. Self-reported barriers to adherence and persistence to treatment with injectable medications for type 2 diabetes. Clin Ther. 2016;38(7):1653-64.

7. Guerci B, Chanan N, Kaur S, Jasso-Mosqueda JG, Lew E. Lack of treatment persistence and treatment nonadherence as barriers to glycaemic control in patients with type 2 diabetes. Diabetes Ther. 2019;10(2):437-49.

Journal Pre-proof 8. Rybelsus [oral semaglutide] package insert. Plainsboro, NJ: Novo Nordisk; 2019.

9. Lorenz M, Evers A, Wagner M. Recent progress and future options in the development of GLP-1 receptor agonists for the treatment of diabesity. Bioorg Med Chem Lett. 2013;15;23(14):4011-4018.

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10. Guja C, Dănciulescu Miulescu R. Semaglutide-the "new kid on the block" in the field of

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glucagon-like peptide-1 receptor agonists?. Ann Transl Med. 2017;5(23):475.

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11. Beglinger C, Poller B, Arbit E, Ganzoni C, Gass S, Gomez-Orellana I, Drewe J.

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concept study in healthy subjects. Clin Pharmacol Ther. 2008 Oct;84(4):468-74.

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12. Ozempic (Semaglutide) [package insert]. Plainsboro, NJ: Novo Nordisk; 2017.

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13. Buckley ST, Bækdal TA, Vegge A, et al. Transcellular stomach absorption of a derivatized

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glucagon-like peptide-1 receptor agonist. Sci Transl Med 2018;10(467). pii: eaar7047.

14. Baekdal TA, Borregaard J, Donsmark M, Breitschaft A, et al. Evaluation of the effects of water volume with dosing and post-dose fasting period on pharmacokinetics of oral semaglutide. Diabetes. 2017;66(Suppl 1):A315.

15. Granhall C, Sondergaard FL, Thomsen M, et al. Pharmacokinetics, safety and tolerability of oral semaglutide in subjects with renal impairment. Clin Pharmacokinet. 2018;57(12):1571-80.

Journal Pre-proof 16. Granhall C, Donsmark M, Golor G, et al. Safety, tolerability, and pharmacokinetics of multiple once-daily dosing of oral semaglutide in healthy males and in males with T2D. Diabetes. 2017;66(Suppl 1):A318.

17. Baekdal TA, Thomsen M, Kupčová V, Hansen CW, Anderson TW. Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment. J Clin

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Pharmacol. 2018;58(10):1314–1323. doi:10.1002/jcph.1131

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18. Bækdal TA, Breitschaft A, Navarria A, Hansen CW. A randomized study investigating the

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effect of omeprazole on the pharmacokinetics of oral semaglutide. Expert Opin Drug Metab

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Toxicol. 2018;14(8):869-77.

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19. Bækdal TA, Borregaard J, Hansen CW, Thomsen M, Anderson TW. Effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin in healthy

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subjects. Clin Pharmacokinet. 2019;58(9):1193-203.

20. Granhall C, Donsmark M, Blicher T, et al, Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes. Clinical Pharmacokinetics. 2019;58(6):781-791.

21. Davies M, Pieber TR, Hartoft-Nielsen ML, et al. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017;318(15):1460–1470.

Journal Pre-proof 22. National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social Sciences and Education. Washington, DC: The National Academies Press; 2010. https://www.ncbi.nlm.nih.gov/books/NBK209904/. Accessed 5 November 2019.

23. Aroda VR, Saugstrup T, Buse JB, Donsmark M, Zacho J, Davies MJ. Incorporating and

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interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1

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randomized clinical trial as an example. Diabetes Obes Metab. 2019;1-8.

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24. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: Randomized Clinical Trial

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Comparing the Efficacy and Safety of Oral Semaglutide Monotherapy with Placebo in Patients

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with Type 2 Diabetes. Diabetes Care. 2019;42(9):1724-32.

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25. Zinman B, Aroda VR, Buse JB, et al. Efficacy, Safety, And Tolerability of Oral Semaglutide Versus Placebo Added to Insulin ± Metformin in Patients with Type 2 Diabetes: the PIONEER 8

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Trial. Diabetes Care 2019 Sept 17. doi: 10.2337/dc19-0898 [Epub ahead of print].

26. Rodbard HW, Rosenstock J, Canani LH, et al. Oral Semaglutide versus Empagliflozin in Patients with Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care 2019 Sept 17. doi: 10.2337/dc-19-0883 [Epub ahead of print].

27. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled with Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA. 2019;321(15):1466-80.

Journal Pre-proof 28. Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with flexible dose adjustments versus sitagliptin in type 2 diabetes (PIONEER 7): a multicenter, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7:528-39.

29. Pratley R, Amod A, Tetens S, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet.

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2019;394:39-50.

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30. Novo Nordisk: Oral semaglutide demonstrates greater reductions in both HbA1c and body

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weight compared to Victoza® in Japanese people with type 2 diabetes PIONEER 9 trial. 2018.

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[cited 2019 October 8]. Available from:

https://www.novonordisk.com/content/Denmark/HQ/www-

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novonordiskcom/en_gb/home/media/news-details.1858145.html

31. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier

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NCT03015220, Safety and Efficacy of Oral Semaglutide Versus Dulaglutide Both in

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Combination With One OAD (Oral Antidiabetic Drug) in Japanese Subjects With Type 2 Diabetes (PIONEER 10); 2019 July 15 [cited 2019 October 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT03015220

32. Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebocontrolled, randomized, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):515-27.

Journal Pre-proof 33. Avgerinos I, Michaeilidis T, Liakos A, et al. Oral semaglutide for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 2019. doi: 10.1111/dom.13899 [epub ahead of print]

34. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes

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in patients with type 2 diabetes. N Engl J Med. 2019;381:841-51.

35. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA Investigators. Lixisenatide in patients with type

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2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–2257.

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36. Holman RR, Bethel MA, Mentz RJ, et al.; EXSCEL Study Group. Effects of once-weekly

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exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–1239.

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37. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med

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2015;373:2117–2128.

38. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03914326, A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL); 2019 Aug 29 [cited 2019 October 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT03914326

39. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306.

Journal Pre-proof 40. Hunt B, Hansen BB, Ericsson Å. Evaluation of the cost per patient achieving treatment targets with oral semaglutide: a short-term cost-effectiveness analysis in the United States. Adv Ther 2019; https://doi.org/10.1007/s12325-019-01125-y

41. Abramson A, Halperin F, Kim J, Traverso G. Quantifying the value of orally delivered biologic therapies: a cost-effectiveness analysis of oral semaglutide. J Pharm Sci

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2019;108(9):3138-45.

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Author Statement

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Trujillo Jennifer: Conceptualization, methodology, writing – original draft preparation, reviewing, editing. Anderson, Sarah: Conceptualization, methodology, writing – original draft preparation, reviewing, editing. Buetel, Trevor: Conceptualization, methodology, writing – original draft preparation, reviewing, editing.

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Conflict of interest: the authors have no conflicts of interest to declare.

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Figure 1. PIONEER Clinical Trial Series Table 1: Summary of Published Phase 3 Randomized Controlled Trials of Oral Semaglutide in Type 2 Diabetes Design

Baseline characteristics

Background treatment

Randomly assigned treatment

PIONEER 1

Randomized, double-blind, placebocontrolled, 26 weeks, n=703

None

Semaglutide 3mg Semaglutide 7mg Semaglutide 14mg Placebo

PIONEER 2

Randomized, open-label, activecontrolled, parallel-group, 52 weeks, n=822 Randomized, double-blind, doubledummy, parallel-group, 78 weeks, n=1864 Randomized, double-blind, doubledummy, 52 weeks, n=711

Mean age, 55 years; A1C, 8.0%; BMI, 31.8 kg/m2; duration of diabetes, 3.5 years Mean age, 58 years; A1C, 8.1%; BMI 32.9 kg/m2; duration of diabetes, 7.4 years

Metformin

Semaglutide 14mg Empagliflozin 25mg

Mean age, 58 years; A1C, 8.3%; BMI, 32.5 kg/m2; duration of diabetes, 8.6 years

Metformin ± SU

Semaglutide 3mg Semaglutide 7mg Semaglutide 14mg Sitagliptin 100mg

Mean age, 56 years; A1C, 8.0%; BMI, 33.0 kg/m2; duration of diabetes, 7.6 years Mean age, 70 years; A1C, 8.0%; BMI 32.4 kg/m2; duration of diabetes, 14 years; eGFR 3059 mL/min/1.73m2 Mean age, 57.4 years; A1C, 8.3%; BMI 31.5 kg/m2; duration of diabetes, 8.8 years Mean age, 61 years; A1C 8.2%; BMI 31 kg/m2; duration of diabetes 15 years

Metformin ± SGLT-2 inhibitor

Randomized, double-blind, 26 weeks, n=324

PIONEER 7

Randomized, open-label, 52 weeks, n=504

PIONEER 8

Randomized, open-label 26 weeks, n=731

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PIONEER 5

-3.8 -3.7

-4.2 -3.8

-0.6 -1.0* -1.3* -0.8

-0.5 -1.1* -1.4* -0.8

-1.2* -2.2* -3.1* -0.6

-1.2* -2.2* -3.3* -0.7

Semaglutide 14mg Liraglutide 1.8mg Placebo

-1.2 -1.1 -0.2

-1.3 -1.1 -0.1

-4.4 -3.1 -0.5

-4.7 -3.2 -0.7

Metformin or SU or both or basal insulin ± metformin

Semaglutide 14mg Placebo

-1.0* -0.2

-1.1* -.01

-3.4* -0.9

-3.7* -1.1

1-2 oral diabetes agents

Semaglutide flexible dose Sitagliptin 100mg

-1.3* -0.8

-1.4* -0.7

-2.6* -0.7

-2.9* -0.8

Insulin (basal, basal/bolus, or premixed) ± metformin

Semaglutide 3mg Semaglutide 7mg Semaglutide 14mg Placebo

-0.6* -0.9* -1.3* -0.1

-0.8* -1.0* -1.4* -0.0

-1.4* -2.4* -3.7* -0.4

-1.3* -3.0* -4.1* -0.4

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-1.4* -0.9

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PIONEER 4

Change in weight from baseline, kg Treatment Trial policy product estimand estimand -1.5 -1.7 -2.3 -2.5* -3.7* -4.1* -1.4 -1.5

-1.3* -0.9

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PIONEER 3

Change in A1C from baseline, % Treatment Trial policy product estimand estimand -0.9* -0.8* -1.2* -1.3* -1.4* -1.5* -0.3 -0.1

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Citation

Abbreviations: AC, active comparator; A1C, glycosylated hemoglobin; BL, baseline; BMI, body mass index; NR, not reported; SGLT-2, sodium glucose co-transporter 2; SU, sulfonylurea *statistically significantly superior to comparator

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Severe or confirmed symptomatic hypoglycemia, No. (%) 5 (2.9) 2 (1.1) 1 (0.6) 1 (0.6)

Discontinuation because of an AE, No. (%)

5 (2.9) 8 (4.6) 12 (6.9) 4 (2.2)

15 (8.6) 9 (5.1) 9 (5.1) 4 (2.2)

30 (7.3) 7 (1.7)

7 (1.7) 8 (2.0)

44 (10.7) 18 (4.4)

45 (9.7) 53 (11.4) 57 (12.3) 37 (7.9)

23 (4.9) 24 (5.2) 36 (7.7) 39 (8.4)

26 (5.6) 27 (5.8) 54 (11.6) 24 (5.2)

43 (15) 31 (11) 11 (8) 17 (10) 6 (4) 22 (9) 8 (3) 2 (1.1) 5 (2.8) 3 (1.7) 1 (0.5)

2 (1) 7 (2) 3 (2) 9 (6) 3 (2) 14 (5.5) 14 (5.6) 52 (28.3) 47 (26) 48 (26.5) 54 (29.3)

31 (11) 22 (8) 15 (11) 24 (15) 8 (5) 22 (9) 8 (3) 13 (7.1) 16 (8.8) 24 (13.3) 5 (2.7)

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Diarrhea, No. (%)

4 (2.3) 7 (4.0) 13 (7.4) 4 (2.2)

38 (9.3) 13 (3.2)

13 (2.8) 28 (6.0) 42 (9.0) 19 (4.1)

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PIONEER Semaglutide 14 (8) 1 3mg 9 (5.1) Semaglutide 28 (16) 7mg 10 (5.6) Semaglutide 14mg Placebo PIONEER Semaglutide 81 (19.8) 2 14mg 10 (2.4) Empagliflozin 25mg PIONEER Semaglutide 34 (7.3) 3 3mg 62 (13.4) Semaglutide 70 (15.1) 7mg 32 (6.9) Semaglutide 14mg Sitagliptin 100mg POINEER Semaglutide 56 (20) 4 Liraglutide 51 (18) Placebo 5 (4) PIONEER Semaglutide 31 (19) 5 Placebo 12 (7) PIONEER Semaglutide 53 (21) 7 Sitagliptin 6 (2) PIONEER Semaglutide 3 (1.6) 8 3mg 5 (2.8) Semaglutide 11 (6.1) 7mg 0 (0) Semaglutide 14mg Placebo Abbreviations: AE, adverse event

Vomiting, No. (%)

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Nausea, No. (%)

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Randomly Assigned Treatment

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Study

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Table 2: Adverse Events Across Phase 3 Randomized Controlled Trials of Oral Semaglutide in Type 2 Diabetes

25 (9) 13 (5) 3 (2) 19 (12) 2 (1) 14 (6) 2 (1) 2 (1.1) 2 (1.1) 5 (2.8) 0 (0)

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Table 3: Comparison of PIONEER 6 and SUSTAIN-6 Citation Design

Numbers of Patients

PIONEE R6

n=1591 oral semagluti de

Baseline characterist ics

Primary Outcome Composi te

Primary outcome: Oral Semagluti de, n (%) 61 (3.8)

Primary outcom e: Placebo , n (%) 76 (4.8)

Hazar d Ratio (95% CI)

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Age ≥ 50 Mean age, First 0.79 years 66 years; occurren (0.57with A1C, 8.2%; ce of 1.1)* establish weight 91 MACE: ed CVD kg; duration death n=1592 or CKD or of diabetes, from CV placebo ≥ 60 15 years causes, years nonfatal with CV MI, risk nonfatal factors stroke SUSTAI Randomiz n=1648 Age ≥ 50 Mean age, First 108 (6.6) 146 0.74 N-6 ed, injectable years 65 years; occurren (8.9) (0.58doublesemagluti with A1C, 8.7%; ce of 0.95) blind, de establish weight 92 MACE: § placeboed CVD kg; duration death controlled, n=1649 or CKD or of diabetes, from CV parallel placebo ≥ 60 13.9 years causes, group years nonfatal trial, 104 with CV MI, weeks risk nonfatal factors stroke Abbreviations: A1C, glycosylated hemoglobin; CKD, chronic kidney disease; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; MACE, major adverse cardiovascular event

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Eventdriven, doubleblind, placebocontrolled, 63.6 weeks

CV Risk Profile

* p<0.001 for noninferiority, p=0.17 for superiority § p<0.001 for noninferiority, p=0.02 for superiority

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Highlights Oral Semaglutide in Type 2 Diabetes

Oral semaglutide is the first FDA-approved glucagon-like peptide-1 receptor agonist.



Oral semaglutide may be an option for patients with type 2 diabetes who require

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

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improved glycemic control, would like to lose weight, and who are not interested in

The PIONEER 5 trial demonstrated efficacy and safety of oral semaglutide in patients

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

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injectable therapy.

with type 2 diabetes and moderate renal impairment. When compared to placebo, the PIONEER 6 trial oral semaglutide demonstrated non-

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

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inferior, but not superior, cardiovascular safety in patients with type 2 diabetes and cardiovascular disease.

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More data are needed to inform the optimal place in therapy of oral semaglutide.

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

Figure 1