The number of glucose-lowering drugs approved for the treatment of type 2 diabetes (T2D) has increased dramatically in the past decade.1 In addition, the focus of T2D management has expanded beyond glycaemic control to encompass other factors, including minimising cardiovascular (CV) risk factors such as overweight/obesity, hypertension and dyslipidemia.2 These are important targets, since the majority (≥85%) of people with diabetes are overweight or obese,3 and people with diabetes have a two- to fourfold increased risk for CV disease (CVD) compared to those without diabetes.4
The glucagon-like peptide 1 (GLP-1) receptor agonists have become an increasingly popular treatment option, due their effectiveness in improving glycaemic control, low hypoglycaemia risk, and potential for weight loss in people with T2D.5 Semaglutide is a recently approved GLP-1 receptor agonist that has proven effective across a wide range of patients with T2D, both in primary and secondary prevention, as a monotherapy with diet and exercise when metformin is contraindicated, or as an add-on to metformin alone or metformin plus sulfonylurea or basal insulin.6 The major barrier to its more widespread use is the need for administration via subcutaneous injection, which is associated with suboptimal adherence.7 Oral semaglutide is the first GLP-1 receptor agonist in a tablet formulation taken once daily. It is co-formulated with the absorption enhancer sodium N-(8-[2-hydroxylbonzoyl] amino) caprylate, which facilitates drug absorption in the stomach by increasing pH, increasing drug solubility and protecting against proteolytic degradation.8
The PIONEER clinical trials for oral semaglutide is a global development program that has enrolled 8,845 people with T2D across 10 clinical trials. PIONEER 1 (NCT02906930) evaluated oral semaglutide in 703 drug-naïve patients with T2D who were not controlled on diet and exercise. Oral semaglutide resulted in clinically meaningful reductions in both HbA1c (all doses) and body weight (higher doses) at week 26. The oral formulation was well tolerated with the most common adverse event being transient mild or moderate nausea.9
The results of several PIONEER trials were announced at the 79th Scientific Sessions of the American Diabetes Association (ADA), which was held from 7 to 11 June 2019, in San Francisco, California. These included studies comparing oral semaglutide with established glucose-lowering agents. PIONEER 2 (NCT02863328) was an open-label study that compared oral semaglutide (14 mg) with empagliflozin in 816 patients with T2D inadequately controlled by metformin. At 26 weeks, people in the oral semaglutide group experienced a statistically significant greater reduction in HbA1c than those receiving empagliflozin (1.9% vs 0.9%). These differences were sustained at 52 weeks (1.3% vs 0.8%).10
PIONEER 4 (NCT02863419), which was simultaneously published in The Lancet,11 was a comparative study of 14 mg oral semaglutide, liraglutide, the most widely used injectable GLP-1 agonist, and placebo in 711 people with T2D inadequately controlled on metformin, with or without an SGLT-2 inhibitor. At weeks 26 and 52, people who received oral semaglutide experienced a statistically significant reduction in HbA1c of 1.3% and 1.2% compared to 1.1% and 0.9% with liraglutide and 0.1% and 0.2% increase with placebo. There were also significant reductions in body weight with oral semaglutide (4.7 and 5.0 kg at 26 and 52 weeks, respectively) compared to 3.2 and 3.1 kg with liraglutide, and 0.7 and 1.2 kg with placebo.11
The PIONEER 7 study (NCT02849080) compared the flexible dose adjustment of oral semaglutide with sitagliptin in 504 people with T2D who were inadequately controlled on 1–2 oral glucose-lowering drugs. In this flexible approach, rather than monthly uptitration from 3 mg to 7 mg to 14 mg, investigators performed a slower titration with the aim of enhancing tolerability. The dose was only increased if patients were considered to need greater HbA1c reduction. At week 52, the oral semaglutide group experienced a statistically significant reduction in HbA1c of 1.4% compared to 0.7% with sitagliptin. This flexible approach was also superior to sitagliptin in terms of the proportion of patients achieving the ADA treatment target of HbA1c <7%. There were also statistically significant reductions in body weight at 52 weeks (2.9 kg for oral semaglutide vs 0.9 kg with sitagliptin).12
PIONEER 5 (NCT02827708) investigated oral semaglutide in patients with T2D and moderate renal impairment (eGFR 30–59 mL/min/1.73 m2). Oral semaglutide did not appear to affect renal function, and was well tolerated. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of -1.0%) and bodyweight (estimated mean change of -3.4 kg).13
In PIONEER 9 (NCT03021187), 731 patients with T2D uncontrolled on insulin with or without metformin were randomly assigned to oral semaglutide 3 mg, 7 mg or 14 mg, or placebo. At weeks 26 and 52, people who received oral semaglutide experienced a statistically significant reduction in HbA1c compared with placebo (estimated changes at week 52 -0.4, -0.8, -1.2 and -0.3% for 3 mg, 7 mg, 14 mg semaglutide and placebo, respectively). The total daily insulin dose was significantly reduced from baseline with oral semaglutide compared with placebo at week 26 (except 3 mg) and week 52.14
However, the most anticipated data were those from PIONEER 6 (NCT02692716), a cardiovascular outcome trial (CVOT) for oral semaglutide that recruited patients with T2D at high risk of CV events (defined as being aged ≥50 years and having established CVD or moderate [stage 3] chronic kidney disease [CKD], or aged ≥60 years with ≥1 other CV risk factor). A total of 3,183 patients were randomised to once-daily oral semaglutide (up to 14 mg) or placebo added to the standard of care. The majority of patients (84.7%) were 50 years of age or older and had CVD or CKD. The primary composite endpoint was time to first occurrence of CV death or non-fatal myocardial infarction (MI) or non-fatal stroke.15
The results, which were simultaneously published in the New England Journal of Medicine,15 showed that death from CV causes occurred in 0.9% of the oral semaglutide group and 1.9% of the placebo group (hazard ratio [HR] 0.49; p=0.03). In terms of individual components of the composite endpoint, oral semaglutide was non-inferior to placebo for non-fatal MI, (2.3% vs 1.9%, respectively; HR 1.18, not significant), and non-fatal stroke, (0.8% and 1.0%, respectively; HR 0.74, not significant). Death from any cause occurred in 1.4% in the oral semaglutide group and 2.8% in the placebo group (HR 0.51; 95% confidence interval, 0.31–0.84).15
In all the PIONEER studies, oral semaglutide was well tolerated, with the most common adverse event being mild to moderate nausea, which diminished over time. Adverse events led to treatment discontinuation in 6–15% of people receiving oral semaglutide.9-15
While the findings of PIONEER 6 were positive, the failure of oral semaglutide to achieve superiority over placebo in terms of cardiac safety raises questions over whether the injectable form of semaglutide is better than the oral form in this aspect. SUSTAIN-6, the CVOT for injectable semaglutide showed a substantial reduction in stroke and some reduction in non-fatal MI.16 However, PIONEER 6 had a relatively short duration of follow-up of just under 16 months and a relatively small study population – 3,183 patients. Consequently, the number of CV events was small, which may explain the failure to achieve statistical significance.
In summary, the findings of the PIONEER studies indicate that oral semaglutide, if approved, will become the only oral GLP-1 therapy for people with T2D. In the future, patients and clinicians may have a choice of taking a pill or a daily injection. The decision will likely depend on patient factors: since oral semaglutide must be taken on an empty stomach 30 minutes prior to food, it might be inconvenient for some patients, and some injectable GLP-1 receptor agonists only need to be administered once weekly. Nevertheless, oral semaglutide represents a valuable addition to the growing list of treatment options for T2D.
- White JR Jr. A brief history of the development of diabetes medications. Diabetes Spectr. 2014;27:82–6.
- American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care. 2018;41:S73–s85.
- Menke A, Rust KF, Fradkin J, et al. Associations between trends in race/ethnicity, aging, and body mass index with diabetes prevalence in the United States: a series of cross-sectional studies. Ann Intern Med. 2014;161:328–35.
- Matheus AS, Tannus LR, Cobas RA, et al. Impact of diabetes on cardiovascular disease: an update. Int J Hypertens. 2013;2013:653789.
- Neumiller JJ. Incretin-based therapies. Med Clin North Am. 2015;99:107–29.
- Goldenberg RM, Steen O. Semaglutide: review and place in therapy for adults with type 2 diabetes. Can J Diabetes. 2019;43:136–45.
- Giorgino F, Penfornis A, Pechtner V, et al. Adherence to antihyperglycemic medications and glucagon-like peptide 1-receptor agonists in type 2 diabetes: clinical consequences and strategies for improvement. Patient Prefer Adherence. 2018;12:707–19.
- Davies M, Pieber TR, Hartoft-Nielsen ML, et al. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. Jama. 2017;318:1460–70.
- Aroda VR, Rosenstock J, Terauchi Y, et al, Effect and safety of oral semaglutide monotherapy in type 2 diabetes—PIONEER 1 trial. Diabetes. 2018;67(Suppl. 1). https://doi.org/10.2337/db18-2-LB.
- Montanya E, Rosenstock J, Canani LH, et al. Oral Semaglutide vs Empagliflozin Added-on to Metformin Monotherapy in Uncontrolled Type 2 Diabetes: PIONEER 2. Presented at: American Diabetes Association 79th Scientific Sessions, San Francisco, CA; 7–11 June 2019. Abstr 54-OR.
- Pratley RE, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019; DOI:https://doi.org/10.1016/S0140-6736(19)31271–1.
- Pieber TR, 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. Lancet Diabetes and Endocrinology. 2019; DOI:https://doi.org/10.1016/S2213-8587(19)30194-9.
- Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes and Endocrinology. 2019; DOI:https://doi.org/10.1016/S2213-8587(19)30192-5.
- Zinman B, Aroda V, Buse JB, et al. 985-P: Oral semaglutide as add-on to insulin in T2D: PIONEER 8. Diabetes. 2019;68 (Suppl. 1): DOI:https://doi.org/10.2337/db19-985-P.
- Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; DOI: 10.1056/NEJMoa1901118
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.
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