Will oral semaglutide be a game-changer in the management of type 2 diabetes in primary care?

Open AccessPublished:August 19, 2020DOI:https://doi.org/10.1016/j.pcd.2020.07.011

      Highlights

      • GLP-1RAs are effective glucose-lowering treatments for people living with T2D.
      • GLP-1RAs may improve cardiovascular outcomes.
      • Oral semaglutide, the first oral GLP-1RA, may increase GLP-1RA use in primary care.
      • Oral semaglutide reduced HbA1c and body weight vs other oral glucose-lowering drugs.
      • Transient gastrointestinal events are associated with oral semaglutide treatment.

      Abstract

      GLP-1 receptor agonists (GLP-1RAs) are recommended for patients with type 2 diabetes (T2D), particularly those at high cardiovascular risk. Oral semaglutide is the first oral GLP-1RA. In clinical trials, oral semaglutide 14 mg reduced mean HbA1c by approximately 1.1–1.5% and reduced body weight by up to 5 kg. These changes were significantly greater compared with empagliflozin, sitagliptin and liraglutide (p < 0.05 for estimated treatment differences at 52 weeks in patients on treatment without rescue medication use). The most common side effects were gastrointestinal, mainly mild-to-moderate and transient nausea. Oral semaglutide may change the paradigm of T2D treatment in primary care.

      Keywords

      1. Introduction

      Patients with type 2 diabetes (T2D) require treatment to be tailored to the individual course of their disease in order to maintain glycaemic control, reduce the risk of diabetes-related comorbidities and improve their prognosis [
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      ]. This may partly be due to the challenge that physicians face in having to navigate complex treatment algorithms and multiple drug classes to provide personalised plans for each patient based on individual clinical factors [
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      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ]. In addition, patients and physicians alike may be reluctant to initiate injectable therapy [
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      In general, patients requiring add-on therapy to metformin are recommended to receive one of a: glucagon-like peptide-1 receptor agonist (GLP-1RA); sodium glucose cotransporter-2 inhibitor (SGLT2i); dipeptidyl peptidase-4 inhibitor (DPP-4i); sulphonylurea (SU) or thiazolidinedione (TZD) [
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      ]. GLP-1RAs or SGLT2is are recommended for patients with indicators of high cardiovascular risk or established cardiovascular disease (CVD), chronic kidney disease (CKD) or heart failure, regardless of glycated haemoglobin (HbA1c) [
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      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
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      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. Of the available treatments, GLP-1RAs are considered among the most effective because they exert multi-organ effects to lower blood glucose, discourage overeating (potentially resulting in body weight reductions) [
      • Peyrot M.
      • Rubin R.R.
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      Addressing barriers to initiation of insulin in patients with type 2 diabetes.
      ] and may reduce cardiovascular risk [
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      Treating psychological insulin resistance in type 2 diabetes.
      ,
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      Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity.
      ,
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      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
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      Liraglutide and cardiovascular outcomes in type 2 diabetes.
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      • Hernandez A.F.
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      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ]. DPP-4is also upregulate GLP-1 by blocking the enzyme responsible for its elimination [
      • Mulvihill E.E.
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      Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors.
      ], but with more modest effects on blood glucose, no effect on body weight [
      • Tran S.
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      • Zinman B.
      • Kramer C.K.
      Efficacy of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors for the management of type 2 diabetes: a meta-analysis of randomized clinical trials.
      ] and with a neutral effect on cardiovascular outcomes [
      • Scirica B.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ,
      • Green J.B.
      • Bethel A.M.
      • Armstrong P.W.
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      ,
      • Rosenstock J.
      • Kahn S.E.
      • Johansen O.E.
      • et al.
      Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial.
      ]. SGLT2is inhibit the action of the transporter largely responsible for glucose reuptake in the kidney and, like GLP-1RAs, improve glucose control, reduce body weight and have cardiovascular benefits [
      • Rieg T.
      • Vallon V.
      Development of SGLT1 and SGLT2 inhibitors.
      ]. TZDs and SUs are effective for glycaemic control and are often preferred when cost is an issue, but are both associated with weight gain and hypoglycaemia, as well as concerns about cardiovascular safety with some (but not all) drugs in these classes [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ].
      Despite their efficacy, global use of GLP-1RAs is low [
      • Dennis J.M.
      • Henley W.E.
      • McGovern A.P.
      • et al.
      Time trends in prescribing of type 2 diabetes drugs, glycaemic response and risk factors: a retrospective analysis of primary care data, 2010–2017.
      ,
      • Montvida O.
      • Shaw J.
      • Atherton J.J.
      • et al.
      Long-term trends in antidiabetes drug usage in the U.S.: real-world evidence in patients newly diagnosed with type 2 diabetes.
      ,
      • Overbeek J.A.
      • Heintjes E.M.
      • Prieto-Alhambra D.
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      Type 2 diabetes mellitus treatment patterns across Europe: a population-based multi-database study.
      ,
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      Treatment patterns and associated factors in 14 668 people with type 2 diabetes initiating a second‐line therapy: results from the global DISCOVER study programme.
      ]. In some cases, cost and lack of reimbursement may contribute to this. However, in primary care in particular, a further barrier may be the reluctance of some injection-naïve patients to accept a subcutaneously administered medication [
      • Santos Cavaiola T.
      • Kiriakov Y.
      • Reid T.
      Primary care management of patients with type 2 diabetes: overcoming inertia and advancing therapy with the use of injectables.
      ]. Such patients also need to be trained properly in injection technique, which could have implications for primary healthcare providers’ time and resource [
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      Are you FIT for purpose? The importance of getting injection technique right.
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      Improvement of insulin injection technique: examination of current issues and recommendations.
      ,
      • Yuan L.
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      Insulin injection technique is associatied with glycemic variability in patients with type 2 diabetes.
      ]. In contrast, DPP-4is, SGLT2is, SUs and TZDs are all administered orally, and there is evidence that adherence to oral therapy is greater than that for injectables [
      • García-Pérez L.E.
      • Alvarez M.
      • Dilla T.
      • et al.
      Adherence to therapies in patients with type 2 diabetes.
      ]. Indeed, since their introduction in 2013, use of oral SGLT2i therapy has been greater than that for injectable GLP-1RAs [
      • Dennis J.M.
      • Henley W.E.
      • McGovern A.P.
      • et al.
      Time trends in prescribing of type 2 diabetes drugs, glycaemic response and risk factors: a retrospective analysis of primary care data, 2010–2017.
      ,
      • Montvida O.
      • Shaw J.
      • Atherton J.J.
      • et al.
      Long-term trends in antidiabetes drug usage in the U.S.: real-world evidence in patients newly diagnosed with type 2 diabetes.
      ], suggesting a preference for oral therapies. The unmet need for an oral GLP-1RA has led to the development of oral semaglutide. This is a coformulation of semaglutide (the subcutaneous formulation of which was more effective than other GLP-1RAs including exenatide [
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial.
      ], dulaglutide [
      • Pratley R.E.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial.
      ] and liraglutide [
      • Capehorn M.S.
      • Catarig A.M.
      • Furberg J.K.
      • et al.
      Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10).
      ]) with the absorption enhancer sodium N‑(8‑[2‑hydroxybenzoyl] amino) caprylate (SNAC) [
      • Buckley S.T.
      • Bækdal T.A.
      • Vegge A.
      • et al.
      Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.
      ] in a tablet. SNAC protects semaglutide from degradation in the stomach and helps to increase its absorption [
      • Buckley S.T.
      • Bækdal T.A.
      • Vegge A.
      • et al.
      Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.
      ] (Fig. 1), thus overcoming two of the main barriers to the oral delivery of a peptide-based molecule [
      • Renukuntla J.
      • Vadlapudi A.D.
      • Patel A.
      • et al.
      Approaches for enhancing oral bioavailability of peptides and proteins.
      ]. Once administered, either orally or by injection, semaglutide has a half-life of approximately one week [
      • Buckley S.T.
      • Bækdal T.A.
      • Vegge A.
      • et al.
      Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.
      ]. However, because of greater variation in drug exposure between individuals with oral versus subcutaneous administration [
      • Buckley S.T.
      • Bækdal T.A.
      • Vegge A.
      • et al.
      Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.
      ], oral semaglutide is dosed once daily rather than the once-weekly schedule used with subcutaneous semaglutide [

      Rybelsus® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ,

      Ozempic® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/ozempic-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ]. Oral semaglutide may be an attractive option for use by primary-care providers (PCPs) and their patients, potentially encouraging earlier and more adherent use of GLP-1RAs to enhance glycaemic control [
      • Abbasi J.
      Oral GLP-1 analog for type 2 diabetes on the horizon.
      ].
      Fig. 1
      Fig. 1Mechanism of absorption for oral semaglutide [
      • Buckley S.T.
      • Bækdal T.A.
      • Vegge A.
      • et al.
      Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.
      ].
      SNAC, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate.
      This article reviews the efficacy and safety of oral semaglutide compared with other recommended glucose-lowering medications and offers practical information on managing oral semaglutide for PCPs, referring to clinical data from the phase 3 PIONEER clinical trial programme.

      2. The phase 3 clinical trial programme for oral semaglutide

      Oral semaglutide was tested in a series of eight global phase 3 clinical trials [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. The programme included patients at different stages of the T2D treatment journey, from those managed by diet and exercise alone, through to people already receiving other oral glucose-lowering drugs and/or insulin, as well as patients with comorbidities such as CVD and CKD [
      • Renukuntla J.
      • Vadlapudi A.D.
      • Patel A.
      • et al.
      Approaches for enhancing oral bioavailability of peptides and proteins.
      ,

      Rybelsus® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ,

      Ozempic® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/ozempic-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ,
      • Abbasi J.
      Oral GLP-1 analog for type 2 diabetes on the horizon.
      ,
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ] (Table 1). In general, patients were eligible for the studies if they were aged ≥18 years, had been diagnosed with T2D at least 90 days before screening and had a HbA1c of ≥7% (53 mmol/mol), i.e. above the American Diabetes Association (ADA) target [
      • American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2019.
      ]. Exclusion criteria varied by trial but generally encompassed disorders including a familial or personal history of certain cancers, including thyroid carcinoma, a history of pancreatitis, and proliferative retinopathy or maculopathy [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ].
      Table 1Overview of the design and key efficacy results of the global PIONEER trials.
      Trial name (N patients)DesignComparatorsKey inclusion criteriaBaseline characteristicsChange in HbA1c
      Data assuming all patients remained on treatment without using rescue medication.
      Change in body weight
      Data assuming all patients remained on treatment without using rescue medication.
      PIONEER 1 (703) [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ]
      ● Double blind

      ● 26 weeks
      ● Oral semaglutide 3, 7, or 14 mg OD

      ● Placebo
      ● Background diet and exercise only

      ● HbA1c 7.0–9.5%
      ● Age: 55 y

      ● T2D duration: 3.5 y

      ● HbA1c: 8.0%

      ● Weight: 88.1 kg
      ● HbA1c (wk 26): –0.8%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –1.3%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –1.5%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 3, 7, or 14 mg) vs –0.1% (placebo)
      ● Body weight (wk 26): –1.7 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –2.5 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –4.1 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 3, 7, or 14 mg) vs –1.5 kg (placebo)
      PIONEER 2 (822) [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ]
      ● Open label

      ● 52 weeks
      ● Oral semaglutide 14 mg OD

      ● Empagliflozin 25 mg OD
      ● Background metformin

      ● HbA1c 7.0–10.5%
      ● Age: 58 y

      ● T2D duration: 7.4 y

      ● HbA1c: 8.1%

      ● Weight: 91.6 kg
      ● HbA1c (wk 26): –1.4%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 14 mg) vs –0.9% (empagliflozin)
      ● Body weight (wk 26): –4.2 kg (oral semaglutide 14 mg) vs –3.8 kg (empagliflozin)
      PIONEER 3 (1864) [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ]
      ● Double blind

      ● 78 weeks
      ● Oral semaglutide 3, 7 or 14 mg OD

      ● Sitagliptin 100 mg OD
      ● Background metformin ± SU

      ● HbA1c 7.0–10.5%
      ● Age: 58 y

      ● T2D duration: 8.6 y

      ● HbA1c: 8.3%

      ● Weight: 91.2 kg
      ● HbA1c (wk 26): –0.5%, –1.1%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –1.4%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 3, 7 or 14 mg) vs –0.8%
      p < 0.05 estimated difference between treatments favouring comparator vs oral semaglutide 3 mg.
      (sitagliptin)
      ● Body weight (wk 26): –1.2 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –2.2 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –3.3 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 3, 7 or 14 mg) vs –0.7 kg (sitagliptin)
      PIONEER 4 (711) [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ]
      ● Double blind

      ● 52 weeks
      ● Oral semaglutide 14 mg OD

      ● Liraglutide 1.8 mg OD

      ● Placebo
      ● Background metformin ± SGLT2i

      ● HbA1c 7.0–9.5%
      ● Age: 56 y

      ● T2D duration: 7.6 y

      ● HbA1c: 8.0%

      ● Weight: 94.0 kg
      ● HbA1c (wk 26): –1.3%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 14 mg) vs –1.1% (liraglutide) and –0.1% (placebo)
      Body weight (wk 26): –4.7 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 14 mg) vs –3.2 kg (liraglutide) and –0.7 kg (placebo)
      PIONEER 5 (324) [
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ]
      ● Double blind

      ● 26 weeks
      ● Oral semaglutide 14 mg OD

      ● Placebo
      ● Moderate renal impairment
      Estimated glomerular filtration rate 30–59 mL/min/1.73 m2.


      ● Background metformin ± SU or insulin ± metformin

      ● HbA1c 7.0–9.5%
      ● Age: 70 y

      ● T2D duration: 14.0 y

      ● HbA1c: 8.0%

      ● Weight: 90.8 kg
      ● HbA1c (wk 26): –1.1%* (oral semaglutide 14 mg) vs –0.1% (placebo)● Body weight (wk 26): –3.7 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 14 mg) vs –1.1 kg (placebo)
      PIONEER 6 (3183) [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]
      ● Double blind

      ● Event driven
      ● Oral semaglutide 14 mg OD

      ● Placebo
      ● ≥50 y with CVD/CKD or ≥60 y with CV risk factors

      ● Background standard of care
      ● Age: 66 y

      ● T2D duration: 14.9 y

      ● HbA1c: 8.2%

      ● Weight: 90.9 kg
      ● HbA1c
      Median time in trial: 15.9 months; difference in outcomes not analysed statistically.
      : –1.0% (oral semaglutide 14 mg) vs –0.3% (placebo)
      ● Body weight
      Median time in trial: 15.9 months; difference in outcomes not analysed statistically.
      : –4.2 kg (oral semaglutide 14 mg) vs –0.8 kg (placebo)
      PIONEER 7 (504) [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ]
      ● Open label

      ● 52 weeks
      With a further 52-week extension trial (results not yet reported).
      ● Oral semaglutide 3, 7 or 14 mg flexibly dosed OD

      ● Sitagliptin 100 mg OD
      ● 1–2 background glucose-lowering therapies

      ● HbA1c 7.5–9.5%
      ● Age: 57 y

      ● T2D duration: 8.8 y

      ● HbA1c: 8.3%

      ● Weight: 88.6 kg
      ● HbA1c (wk 52): –1.4%* (oral semaglutide) vs –0.7% (sitagliptin)● HbA1c (wk 52): –2.9 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide) vs –0.8 kg (sitagliptin)
      PIONEER 8 (731) [
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]
      ● Double blind

      ● 52 weeks
      ● Oral semaglutide 3, 7 or 14 mg OD

      ● Placebo
      ● Background insulin

      ● HbA1c 7.0–9.5%
      ● Age: 61 y

      ● T2D duration: 15.0 y

      ● HbA1c: 8.2%

      ● Weight: 85.9 kg
      ● HbA1c (wk 26): –0.6%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –1.0%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –1.4%
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 3, 7 or 14 mg) vs –0.0 (placebo)
      ● Body weight (wk 26): –1.3 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –3.0 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      , –4.1 kg
      p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      (oral semaglutide 3, 7 or 14 mg) vs –0.4 kg (placebo)
      CKD, chronic kidney disease; CV(D), cardiovascular (disease); HbA1c, glycated haemoglobin; OD, once daily; SGLT2i, sodium glucose cotransporter-2 inhibitor; SU, sulphonylurea; T2D, type 2 diabetes; wk, week; y, year.
      * p < 0.05 for estimated difference between treatments favouring oral semaglutide vs comparator.
      p < 0.05 estimated difference between treatments favouring comparator vs oral semaglutide 3 mg.
      a Data assuming all patients remained on treatment without using rescue medication.
      b Estimated glomerular filtration rate 30–59 mL/min/1.73 m2.
      c Median time in trial: 15.9 months; difference in outcomes not analysed statistically.
      d With a further 52-week extension trial (results not yet reported).
      Early clinical trials showed that absorption of oral semaglutide was affected by food and water intake [
      • Buckley S.T.
      • Bækdal T.A.
      • Vegge A.
      • et al.
      Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist.
      ]. Therefore, to ensure adequate absorption, oral semaglutide was dosed in the morning on an empty stomach with no more than 120 mL water, and at least 30 min before any other oral medication, food or other drink [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. Based on a phase 2 trial [
      • Davies M.
      • Pieber T.R.
      • Hartoft-Nielsen M.
      • Hansen O.K.H.
      • Jabbour S.
      • Rosenstock J.
      Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial.
      ], the dose was escalated in 4-week increments, starting at 3 mg once daily, to mitigate potential gastrointestinal (GI) side effects, which are the most common type of adverse event with GLP-1RAs [
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial.
      ,
      • Pratley R.E.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial.
      ,
      • Capehorn M.S.
      • Catarig A.M.
      • Furberg J.K.
      • et al.
      Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10).
      ].
      Data from the PIONEER trials were analysed using two sets of prespecifications (called estimands) to provide an estimated treatment effect based on whether or not data from patients who discontinued treatment or required rescue (i.e. additional glucose-lowering) medication during the trial were included in the efficacy analyses [
      • Aroda V.R.
      • Saugstrup T.
      • Buse J.B.
      • et al.
      Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: the PIONEER 1 randomized clinical trial as an example.
      ]. Here, we present efficacy data without the confounding effects of treatment discontinuation or rescue medication use (called the trial product estimand in the PIONEER trials), i.e. showing the best efficacy achievable with oral semaglutide [
      • Aroda V.R.
      • Saugstrup T.
      • Buse J.B.
      • et al.
      Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: the PIONEER 1 randomized clinical trial as an example.
      ].

      3. Efficacy of oral semaglutide in patients who require treatment intensification

      The European Association for the Study of Diabetes (EASD) and ADA joint consensus report [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ] states that patients without a high cardiovascular risk, inadequately controlled on metformin, should receive one of a DPP-4i, GLP-1RA, SGLT2i, SU or TZD as add-on therapy. Glucose-lowering drugs from other classes can then be added as needed (with some restrictions) to achieve further HbA1c reductions [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. However, there is little guidance regarding the order in which medications should be added [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. Four of the PIONEER trials were designed with this clinical choice in mind, evaluating oral semaglutide against commonly used oral DPP-4i and SGLT2i medications, as well as a subcutaneously administered GLP‑1RA [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ].

      3.1 Oral semaglutide vs SGLT2i

      In PIONEER 2, oral semaglutide 14 mg once daily was compared against empagliflozin 25 mg once daily in patients receiving metformin who had an average T2D duration of approximately 7 years, a mean HbA1c of 8.1% and a baseline body weight of approximately 92 kg [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ]. Oral semaglutide provided significantly greater reductions in HbA1c at 26 weeks compared with empagliflozin (–1.4% vs –0.9%; p < 0.0001) (Table 1). Importantly, significantly better glycaemic control with oral semaglutide was maintained at 52 weeks (–1.3% vs –0.8%; p < 0.0001) (Fig. 2), and 72% of patients receiving oral semaglutide (vs 48% on empagliflozin) had a HbA1c <7% at the end of treatment (p < 0.0001) [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ]. Both treatments led to a decrease in body weight at 26 weeks (–4.2 kg vs –3.8 kg; p = 0.1358) (Table 1), but whereas weight did not decrease further in patients receiving empagliflozin, those taking oral semaglutide had a further reduction at week 52 (–4.7 kg vs –3.8 kg; p = 0.0114 vs empagliflozin) (Fig. 3) [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ].
      Fig. 2
      Fig. 2Change in HbA1c with oral semaglutide and active comparators at end of treatment (PIONEER 2, 3 and 4) [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ].
      Data analysed assuming patients remained on treatment without use of rescue medication. *p < 0.05 favouring oral semaglutide versus comparator for estimated treatment difference. HbA1c, glycated haemoglobin.
      Fig. 3
      Fig. 3Change in body weight with oral semaglutide vs active comparators at end of treatment (PIONEER 2, 3 and 4) [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ].
      Data analysed assuming patients remained on treatment without use of rescue medication. *p < 0.05 favouring oral semaglutide versus comparator for estimated treatment difference.

      3.2 Oral semaglutide vs DPP-4i

      Three doses of oral semaglutide (3, 7 and 14 mg once daily) and a flexible dosing approach were compared against sitagliptin 100 mg once daily in patients uncontrolled on 1–2 oral glucose-lowering medications [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ]. Patients in these two trials (PIONEER 3 and 7) had T2D for 8–9 years, with HbA1c 8.3% and body weight of approximately 90 kg at baseline [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ]. Compared with sitagliptin (–0.8%), there were significant HbA1c reductions from baseline with oral semaglutide 7 mg (–1.1%; p < 0.001) and 14 mg (–1.4%; p < 0.001), but not oral semaglutide 3 mg (–0.5%; p < 0.001 favouring sitagliptin), at week 26 in PIONEER 3 (Table 1). Significant reductions in HbA1c versus sitagliptin were maintained at week 78 for the 7 and 14 mg doses (Fig. 2) [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ]. When oral semaglutide was flexibly dosed in PIONEER 7, 63% of patients reached the HbA1c target of <7% compared with sitagliptin (28%; p < 0.0001) after 52 weeks [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ]. Oral semaglutide 7 mg (–2.2 kg) and 14 mg (–3.3 kg) significantly reduced body weight from baseline versus sitagliptin (–0.7 kg) at week 26 (p < 0.001) (Table 1), with the difference conserved at week 78 (Fig. 3) [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ]. Flexibly dosed oral semaglutide also led to significantly greater body weight loss than sitagliptin after 52 weeks (–2.9 kg vs –0.8 kg; p < 0.0001) (Table 1) [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ].

      3.3 Oral semaglutide vs injectable GLP-1RA

      In PIONEER 4, people with T2D uncontrolled on metformin with or without an SGLT2i received either oral semaglutide 14 mg once daily or the injectable GLP-1RA liraglutide escalated to 1.8 mg once daily [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ]. There was also a placebo arm. Participants had a T2D duration of approximately 7–8 years, mean HbA1c 8.0% and body weight 94 kg at baseline [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ]. At 26 weeks, patients receiving oral semaglutide had a significantly greater reduction from baseline in HbA1c (–1.3%) than those receiving liraglutide (–1.1%; p = 0.0056) (Table 1) and a significant difference between treatments remained at week 52 (Fig. 2) [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ]. Similarly, body weight loss from baseline with oral semaglutide was significantly greater than with liraglutide (–4.7 kg vs –3.2 kg and –5.0 kg vs –3.1 kg at weeks 26 and 52, respectively, p < 0.0001 for both weeks) (Table 1, Fig. 3) [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ].

      4. Efficacy of oral semaglutide in patients with long-standing T2D and comorbidities

      The EASD/ADA consensus report and the European Society of Cardiology guidelines state that, independent of the target HbA1c, people with T2D and atherosclerotic CVD or CKD should preferentially receive a GLP-1RA with proven benefit in reducing cardiovascular risk and/or CKD progression [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. An SGLT2i may also be considered. Further medications that do not increase cardiovascular risk can be added in a stepwise fashion (as in other patients) when increased glycaemic control is required [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. SGLT2is are preferred over GLP-1RAs in patients with heart failure and/or CKD (and both drug classes can be combined if clinically appropriate) [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. Unlike SGLT2is, there is no restriction for use of GLP-1RAs in patients with renal impairment [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. If glycaemic control continues to decline in patients taking multiple glucose-lowering therapies, insulin can be added [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ].
      Three PIONEER trials were designed to study oral semaglutide in patients with CVD and/or CKD, and in those taking insulin [
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. In PIONEER 5, in patients with moderate renal impairment (estimated glomerular filtration rate 30–59 mL/min/1.73 m2) who were taking other glucose-lowering drugs and/or insulin, oral semaglutide had significantly greater efficacy for HbA1c and body weight reduction compared with background medication alone (Table 1) [
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ]. Coadministration with oral semaglutide also led to reductions in insulin doses in PIONEER 8 [
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. There were also reductions in HbA1c and body weight with oral semaglutide added on to standard of care in patients who had established CVD or were at high cardiovascular risk, compared with standard care alone in PIONEER 6 (Table 1) [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ].

      5. Safety of oral semaglutide in the PIONEER programme

      In the PIONEER trials, oral semaglutide had a tolerability profile consistent with that seen for other GLP-1RAs, including once-weekly subcutaneous semaglutide [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ,
      • Aroda V.R.
      • Ahmann A.
      • Cariou B.
      • et al.
      Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: insights from the SUSTAIN 1–7 trials.
      ]. The most common adverse events were GI-related, mainly nausea, vomiting and diarrhoea, which generally occurred early in treatment, and mostly resolved after continuous use (Table 2) [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. When flexible dose adjustment of oral semaglutide was employed, with dose reduction permitted if gastrointestinal tolerability warranted (PIONEER 7), most patients were on an effective oral semaglutide dose (either 7 mg [30% of patients] or 14 mg [59% of patients]) at the end of treatment [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ] (Table 2). There were no unexpected safety concerns across the PIONEER trials, including in patients with moderate renal impairment (PIONEER 5) [
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ]. Additionally, across the PIONEER trials, there was a low incidence of severe or blood glucose-confirmed symptomatic hypoglycaemia (1.7% in PIONEER 2 and 0.7% in PIONEER 4), although the incidence was higher in patients receiving concomitant SU and insulin, both of which are associated with hypoglycaemia [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. Patients with active diabetic retinopathy were excluded from the trials, and the incidence of diabetic retinopathy in-trial was low (<8% and not related to dose) [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. Most cases were not symptomatic and were found by routine eye inspections.
      Table 2Summary of safety results for the PIONEER studies.
      Trial name (N patients)Any AE (%)Most common GI AEs (%)AEs leading to treatment discontinuation (%)On-treatment hypoglycaemia
      Considered severe by American Diabetes Association criteria, symptomatic and/or confirmed by blood glucose <3.1 mmol/L (56 mg/dL).
      (%)
      In-trial CV events (%)
      PIONEER 1 (703) [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ]
      • 58%, 53%, 57% (oral semaglutide 3, 7, 14 mg) vs 56% (placebo)• Nausea: 8%, 5%, 16% vs 6%

      • Diarrhoea: 9%, 5%, 5% vs 2%

      • Vomiting: 3%, 5%, 7% vs 2%
      • Any: 2%, 4%, 7% vs 2%

      • GI: 2%, 2%, 5% vs 1%
      • 3%, 1%, 1% vs 1%• 2%, 3%, 1% vs 3%
      Confirmed by an independent adjudication committee.
      PIONEER 2 (822) [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ]
      • 70% (oral semaglutide 14 mg) vs 69% (empagliflozin)• Nausea: 20% vs 2%

      • Diarrhoea: 9% vs 3%

      • Vomiting: 7% vs 2%
      • Any: 11% vs 4%

      • GI: 8% vs 1%
      • 2% vs 2%• 1% vs 2%
      Confirmed by an independent adjudication committee.
      PIONEER 3 (1864) [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ]
      • 79%, 78%, 80% (oral semaglutide 3, 7, or 14 mg) vs 83% (sitagliptin)• Nausea: 7%, 13%, 15% vs 7%

      • Diarrhoea: 10%, 11%, 12% vs 8%

      • Vomiting: 3%, 6%, 9% vs 4%
      • Any: 6%, 6%, 12% vs 5%

      • GI: 2%, 3%, 7% vs 3%
      • 5%, 5%, 8% vs 8%• 3%, 2%, 1% vs 2%
      Confirmed by an independent adjudication committee.
      PIONEER 4 (711) [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ]
      • 80% (oral semaglutide 14 mg) vs 74% (liraglutide) and 67% (placebo)• Nausea: 20% vs 18% and 4%

      • Diarrhoea: 15% vs 11% and 8%

      • Vomiting: 9% vs 5% and 2%
      • Any: 11% vs 9% and 4%

      • GI: 8% vs 6% and 2%
      • 1% vs 2% and 2%• 1% vs 1% and 1%
      Confirmed by an independent adjudication committee.
      PIONEER 5 (324) [
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ]
      • 74% (oral semaglutide 14 mg) vs 65% (placebo)• Nausea: 19% vs 7%

      • Constipation: 12% vs 4%

      • Vomiting: 12% vs 1%
      • Any: 15% vs 5%

      • GI: 12% vs 2%
      • 6% vs 2%• 3% vs 2%
      Confirmed by an independent adjudication committee.
      PIONEER 6 (3183)
      Patients in PIONEER 6 were at high CV risk.
      [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]
      • NR• NR• Any: 12% vs 7%

      • GI: 7% vs 2%
      • NR• 4% vs 5%
      First major CV AE, i.e. CV death, non-fatal myocardial infarction or nonfatal stroke.
      PIONEER 7 (504) [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ]
      • 78% (oral semaglutide flex) vs 69% (sitagliptin)• Nausea: 21% vs 2%

      • Diarrhoea: 9% vs 3%

      • Vomiting: 6% vs 1%
      • Any: 9% vs 3%

      • GI: 6% vs 1%
      • 6% vs 6%• 1% vs 2%
      Confirmed by an independent adjudication committee.
      PIONEER 8 (731) [
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]
      • 74%, 78%, 83% (oral semaglutide 3, 7, or 14 mg) vs 76% (placebo)• Nausea: 11%, 17%, 23% vs 7%

      • Diarrhoea: 9%, 12%, 15% vs 6%

      • Vomiting: 6%, 8%, 10% vs 4%
      • Any: 7%, 9%, 13% vs 3%

      • GI: 5%, 7%, 10% vs 1%
      • 28%, 26%, 27% vs 29%• 2%, 3%, 3% vs 3%
      Confirmed by an independent adjudication committee.
      Proportions are percentages of patients with at least one event.
      AE, adverse event; CV, cardiovascular; flex, flexibly dosed; GI, gastrointestinal; NR, not recorded.
      a Considered severe by American Diabetes Association criteria, symptomatic and/or confirmed by blood glucose <3.1 mmol/L (56 mg/dL).
      b Confirmed by an independent adjudication committee.
      c Patients in PIONEER 6 were at high CV risk.
      d First major CV AE, i.e. CV death, non-fatal myocardial infarction or nonfatal stroke.
      GLP-1RAs or SGLT2is are recommended for patients at high cardiovascular risk, regardless of HbA1c [
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. PIONEER 6 was a pre-approval trial specifically designed to evaluate the cardiovascular safety of oral semaglutide when added to standard of care, compared with standard care alone [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]. Patients were either aged ≥50 years with established CVD and/or CKD, or ≥60 years with cardiovascular risk factors. Over a median 15.9 months of study, adding oral semaglutide to standard care was shown to be as safe as standard care alone. There was no increase in the risk of major adverse cardiovascular events (defined as first instance of cardiovascular death, nonfatal stroke or nonfatal myocardial infarction) with versus without oral semaglutide (3.8% vs 4.8%, p < 0.001 for noninferiority) [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]. With subcutaneous semaglutide, as well as liraglutide, dulaglutide and albiglutide, a benefit of adding GLP-1RA to standard of care has been seen in terms of reductions in the risk of major adverse cardiovascular events [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ]. The 5-year SOUL trial (NCT03914326) is now underway to determine whether oral semaglutide also has a cardiovascular benefit in people with T2D and CVD or CKD.

      6. Practical considerations for oral semaglutide use in the primary care setting

      A practical algorithm for PCPs who are considering prescribing oral semaglutide, based on international recommendations, is provided in Fig. 4.
      Fig. 4
      Fig. 4Potential place of oral semaglutide in international treatment recommendations for people with T2D.
      aWith established CV disease, CKD or risk factors; bAt end of treatment in patients who remained on treatment and did not use rescue medication in PIONEER 2–4 [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ]; cMetformin alone in PIONEER 2 [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ], metformin ± SU in PIONEER 3 [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ], metformin ± SGLT2i in PIONEER 4 [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ] and 1–2 of metformin, SU, TZD or SGLT2i in PIONEER 7 [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ]; dGuidance varies by drug and region; eGLP-1RAs and DPP4is are not recommended to be used in combination; fConsider basal insulin with lower risk of hypoglycaemia; gBasal, bolus and premix insulin.
      CKD, chronic kidney disease; CV, cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; HF, heart failure; OAD, oral anti-diabetes (glucose-lowering) drug; SGLT2i, sodium glucose cotransporter-2 inhibitor; SU, sulphonylurea; T2D, type 2 diabetes; TZD, thiazolidinediones.

      6.1 Patients requiring improved glycaemic control

      Oral semaglutide may encourage more PCPs and their patients to consider GLP-1RA therapy as an add-on to metformin when treatment intensification is needed. Although international recommendations give limited guidance as to which drug class to choose first in this case [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ], the results of the PIONEER trials suggest that oral semaglutide is as effective as an injectable GLP-1RA, and physicians could consider adding oral semaglutide before an SGLT2i or DPP-4i because of greater HbA1c reductions in head-to-head trials [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ]. Equally, many patients in PIONEER 7 were already taking an SGLT2i and/or TZD [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ], supporting the addition of oral semaglutide to these regimens. Because of the overlap in their modes of action, the combination of oral semaglutide and a DPP-4i was not tested, and indeed is not advocated by recommendations [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ].

      6.2 Patients requiring improved body weight control

      For patients at low cardiovascular risk, for whom body weight control or reduction and intensification of glycaemic control are important, the EASD/ADA consensus is to add a GLP-1RA or SGLT2i with proven weight-loss efficacy as second line to metformin [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]. Oral semaglutide was more effective than liraglutide for weight loss in PIONEER 4 [
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ]. When compared head-to-head in PIONEER 2, both oral semaglutide and the SGLT2i empagliflozin helped to reduce body weight by approximately 4 kg after 26 weeks’ treatment [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ]. However, whereas weight loss plateaued with empagliflozin, it continued decreasing with oral semaglutide up to week 52 in patients who continued on treatment without needing rescue medication, at which point it approached an average of approximately 5 kg [
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ]. Therefore, oral semaglutide can be considered as an effective option for patients in this situation.

      6.3 Patients at high cardiovascular risk or with established CVD/CKD

      The situation in people with T2D and concomitant CVD and/or CKD, or who are considered at increased cardiovascular risk is somewhat nuanced. Unless considered inappropriate, and regardless of HbA1c target, such patients are recommended to receive a GLP-1RA with proven cardiovascular benefit [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ], which in practice means subcutaneous semaglutide, dulaglutide or liraglutide [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ]. Oral semaglutide demonstrated cardiovascular safety in high-risk patients [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ], and conclusive evidence of a benefit over current standard of care will come with the completion of the long-term SOUL trial. Therefore, PCPs considering oral semaglutide in patients at high cardiovascular risk will have to weigh up their patients’ preferences for an oral versus injectable therapy against the current evidence and the option to use an injectable GLP-1RA or oral SGLT2i with proven cardiovascular benefit instead [
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • et al.
      2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ].

      6.4 Patients with comorbidities

      It should be noted that oral semaglutide does not require dose adjustment in patients with hepatic or renal impairment (including people receiving dialysis) [
      • Granhall C.
      • Søndergaard F.L.
      • Thomsen M.
      • Anderson T.W.
      • et al.
      Pharmacokinetics, safety and tolerability of oral semaglutide in subjects with renal impairment.
      ,
      • Bækdal T.A.
      • Thomsen M.
      • Kupčová V.
      • et al.
      Pharmacokinetics, safety, and tolerability of oral semaglutide in subjects with hepatic impairment.
      ,

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ]. In contrast, SGLT2is have adjustments and restrictions for use in patients with impaired liver and/or kidney function [

      Jardiance® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_en.pdf. (Accessed 23 January 2020).

      ,

      Jardiance® US Prescribing Information. Available at: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf. (Accessed 23 January 2020).

      ,

      Invokana® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/invokana-epar-product-information_en.pdf. (Accessed 23 January 2020).

      ,

      Invokana® US Prescribing Information. Available at: http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf. (Accessed 23 January 2020).

      ]. There were no clinically significant drug–drug interactions between oral semaglutide and commonly coadministered drugs (digoxin, lisinopril, metformin, warfarin and the combined oral contraceptive) [

      A.B. Jordy, A. Breitschaft, E. Christiansen, et al. Oral semaglutide does not affect the bioavailability of the combined contraceptive ethinylestradiol/levonorgestrel. Paper presented at: 54th Annual Meeting of the European Association for the Study of Diabetes (EASD), 1–5 October 2018; Berlin, Germany.

      ,
      • Bækdal T.A.
      • Borregaard J.
      • Hansen C.W.
      • et al.
      Effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin in healthy subjects.
      ]. Moreover, coadministration of a proton pump inhibitor (omeprazole) did not affect oral semaglutide exposure to a clinically relevant extent [
      • Bækdal T.A.
      • Breitschaft A.
      • Navarria A.
      • Hansen C.W.
      A randomized study investigating the effect of omeprazole on the pharmacokinetics of oral semaglutide.
      ]. However, exposure to levothyroxine was increased by 33% when coadministered with oral semaglutide (see dosing instructions below) [
      • Hauge C.
      • Breitschaft A.
      • Hartoft-Nielsen M.
      • Jensen S.
      • Bækdal T.A.
      A drug-drug interaction trial of oral semaglutide with levothyroxine and multiple coadministered tablets.
      ]. The presence of upper GI disease did not affect the pharmacokinetics of oral semaglutide [

      J.J. Meier, C. Granhall, U. Hoevelmann, et al., Effect of upper gastrointestinal disease on the pharmacokinetics of oral semaglutide in subjects with type 2 diabetes. Paper presented at: 79th Annual Scientific Sessions of the American Diabetes Association, 7–11 June 2019; San Francisco, USA. Abstract 1013-P.

      ].
      The US prescribing information states to avoid oral semaglutide in patients with a personal or familial history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2 [

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ]. Oral semaglutide should be discontinued in cases of suspected pancreatitis, and renal function should be monitored in patients with renal impairment reporting severe adverse GI reactions [

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ]. Patients with a history of diabetic retinopathy should also be monitored closely with regular screening for progression of diabetic retinopathy. The incidence of hypoglycaemia was noticeably higher when oral semaglutide was combined with insulin [
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ], so consideration should be given to lowering the insulin dose in this circumstance [

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ].

      6.5 Dosing instructions

      Patients should be instructed to take oral semaglutide in the morning upon waking (i.e. in a fasted state) with no more than 120 mL/4 fl oz (half a glass) of water, and to wait at least 30 min before eating breakfast, consuming any further liquid or taking any other oral medication (Fig. 5) [

      Rybelsus® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ,

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ]. This approach ensures clinically relevant semaglutide exposure [
      • Donsmark M.
      • Borregaard J.
      • Breitschaft A.
      • et al.
      Evaluation of the effects of water volume with dosing and post-dose fasting period on pharmacokinetics of oral semaglutide.
      ,
      • Maarbjerg S.J.
      • Breitschaft A.
      • Søndergaard F.
      • et al.
      Evaluation of the effect of food on the pharmacokinetics of oral semaglutide.
      ]. If patients are taking comedications with similar dosing instructions (such as thyroid hormone), consideration should be given as to whether these medications can be taken at a different time of day (potentially at bedtime [
      • Jonklaas J.
      • Bianco A.C.
      • Bauer A.J.
      • et al.
      Guidelines for the treatment of hypothyroidism.
      ]). Compliance with the dosing conditions for oral semaglutide with monitoring of thyroid parameters is strongly advised, as is treatment of hypothyroidism according to local guidelines.
      Fig. 5
      Fig. 5Treatment algorithm for oral semaglutide [

      Rybelsus® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ,

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ,
      • Kruger D.F.
      • Bode B.
      • Spollett G.R.
      Understanding GLP-1 analogs and enhancing patient success.
      ,
      • Du Y.T.
      • Rayner C.K.
      • Jones K.L.
      • et al.
      Gastrointestinal symptoms in diabetes: prevalence, assessment, pathogenesis, and management.
      ].
      GI, gastrointestinal; HbA1c, glycated haemoglobin.
      As in the PIONEER trials, patients should start on an oral semaglutide dose of 3 mg once daily, escalated to 7 mg after 30 days. If further glycaemic control is needed, the dose can be increased to 14 mg once daily after a further 30 days (Fig. 5) [

      Rybelsus® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ,

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ]. The 14 mg once-daily oral dose is considered equivalent to the 0.5 mg once-weekly subcutaneous dose [

      Rybelsus® EU Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf. (Accessed 8 June 2020).

      ,

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ]. The US prescribing information for oral semaglutide recommends that patients currently treated with subcutaneous semaglutide 0.5 mg once weekly can be switched to oral semaglutide by starting oral semaglutide 7 mg or 14 mg once daily up to 7 days after the last semaglutide injection [

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ]. There is no equivalent oral dose to the subcutaneous 1 mg dose of semaglutide. If a patient treated with oral semaglutide 14 mg needs to transition to subcutaneous semaglutide, perhaps to achieve greater glycaemic efficacy, the US prescribing information recommends starting injections, initially at 0.5 mg once weekly, on the day after the last oral semaglutide dose [

      Rybelsus® US prescribing information (updated January 2020). Available at: https://www.novo-pi.com/rybelsus.pdf. (Accessed 23 January 2020).

      ].

      6.6 Managing potential GI side effects

      GI side effects were dose-dependent in the PIONEER trials, but at the highest dose fewer than 25% of patients experienced nausea; diarrhoea and vomiting tended to occur at incidences <15% [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ,
      • Rodbard H.W.
      • Rosenstock J.
      • Canani L.H.
      • et al.
      Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial.
      ,
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ,
      • Pratley R.
      • Amod A.
      • Hoff S.T.
      • et al.
      Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      ,
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ,
      • Zinman B.
      • Aroda V.R.
      • Buse J.B.
      • et al.
      Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial.
      ]. In PIONEER 3, such events tended to occur early in treatment and when the dose was escalated; nausea associated with oral semaglutide 14 mg lasted for a median 21 days, whereas diarrhoea lasted 9 days and vomiting 2 days [
      • Rosenstock J.
      • Allison D.
      • Birkenfeld A.L.
      • 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.
      ]. It is therefore recommended that patients are advised of the possibility of these events occurring during the first weeks of oral semaglutide treatment, and also potentially when the dose is escalated (Fig. 5). Patients should be reassured that, in most cases, these symptoms are not severe and will resolve on their own after a few weeks, and that they should continue their treatment. If needed, nausea may be relieved by use of natural supplements such as ginger or peppermint, avoiding fried or fatty foods or by reducing meal portion size (Fig. 5) [
      • Kruger D.F.
      • Bode B.
      • Spollett G.R.
      Understanding GLP-1 analogs and enhancing patient success.
      ]. Nevertheless, if symptoms are severe or persistent, patients should be encouraged to inform their PCP and consideration could be given to temporary dose adjustment or withdrawal of either metformin (which is also associated with GI issues [
      • Du Y.T.
      • Rayner C.K.
      • Jones K.L.
      • et al.
      Gastrointestinal symptoms in diabetes: prevalence, assessment, pathogenesis, and management.
      ]) or oral semaglutide until symptoms resolve (Fig. 5). Notably, oral semaglutide was effective when flexible dose adjustment was used [
      • Pieber T.R.
      • Bode B.
      • Mertens A.
      • et al.
      Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.
      ] and in the absence of metformin [
      • Aroda V.R.
      • Rosenstock J.
      • Terauchi Y.
      • et al.
      PIONEER 1: randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes.
      ].

      7. Conclusion

      In clinical trials, oral semaglutide 14 mg reduced mean HbA1c by approximately 1.1–1.5% and reduced body weight by up to 5 kg. The most common side effects were gastrointestinal, mainly mild-to-moderate and transient nausea. Oral semaglutide may offer a practical and effective means of managing people living with T2D who require treatment intensification, and may change the paradigm of care in the primary care setting.

      Conflicts of interest

      SS reports personal fees from Amgen, AstraZeneca, NAPP, Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Sanofi-Aventis and Boehringer Ingelheim, grants from AstraZeneca, Sanofi-Aventis, Servier and Janssen, outside the submitted work.
      LM reports personal fees from Novo Nordisk, outside the submitted work.
      MK reports personal fees from Novo Nordisk, outside the submitted work.
      KK reports personal fees from Amgen, AstraZeneca, Bayer, NAPP, Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Berlin-Chemie AG/Menarini Group, Sanofi-Aventis, Servier and Boehringer Ingelheim, grants from Pfizer, Boehringer Ingelheim, AstraZeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme and Servier, outside the submitted work.

      Role of the funding source

      The authors are solely responsible for developing the content of this manuscript with the support of the medical writer, funded by Novo Nordisk A/S. The funder (Novo Nordisk A/S) was not involved in directing the content, but was given the opportunity to review an advanced draft for the purposes of ensuring medical accuracy.

      Acknowledgements

      The authors would like to thank Stephen Purver of Axis, a division of Spirit Medical Communications Group Limited, for medical writing and editorial assistance, funded by Novo Nordisk A/S and Karen Boje Pedersen of Novo Nordisk for performing a medical accuracy review of the content.
      KK and SS acknowledge support from the National Institute for Health Research Applied Research and Care – East Midlands (NIHR ARC – EM) and the Leicester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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