PIONEER 5 Study Validates Oral GLP-1 Effectiveness

The PIONEER 5 study discusses the safety and efficacy of the first oral GLP-1 receptor agonist, a potential substitute to injections. 

Many people with type 2 diabetes can develop renal impairment which in turn can lead to a restriction in their treatment options for diabetes, as many common oral glucose-lowering drugs have restrictions for use in people with decreased kidney function. Chronic kidney disease is also associated with hypoglycemia and many patients may be taking glucose-lowering drugs that are associated with an increased risk of hypoglycemia and weight gain. Some studies have shown the effectiveness and safety of GLP-1 agonists such as Liraglutide (superior to placebo) and dulaglutide (similar efficacy compared with insulin) without a negative effect on renal function; however, they are administered subcutaneously which might not be ideal for some patients. Oral semaglutide monotherapy has shown promising results as it significantly decreased HbA1C and body weight compared to placebo in patients with type 2 diabetes not controlled through diet and exercise. In patients without diabetes, renal impairment did not affect the pharmacokinetics of oral semaglutide. A phase 3a trial, PIONEER 5, aimed to study the efficacy and safety of oral semaglutide, the first oral GLP-1 agonist, in patients with type 2 diabetes and moderate renal impairment.

The PIONEER 5 study was a multicenter, double-blind, randomized, placebo-controlled, phase 3a trial where 324 participants, age ≥18yrs, with type 2 diabetes, HbA1C 7.0-9.0% and moderate renal impairment (eGFR 30-59 mL/min/1.732), were randomly assigned to receive either once-daily oral semaglutide on an empty stomach with up to half a glass of water and 30min before any food/beverage/medication, or placebo for 26 weeks with a follow up period of 5 weeks, with their standard glucose-lowering medication. To improve gastrointestinal tolerability, oral semaglutide was initiated at 3mg, escalated to 7mg in 4 weeks then increased to 14mg at 8 weeks.

Briefly, to test the superiority and efficacy of oral semaglutide versus placebo, the primary endpoint of the study was set to HbA1C change from baseline to week 26 and confirmatory secondary outcome was the change in body weight from baseline to week 26. Safety endpoints included the number of treatment-emergent adverse events, and symptomatic hypoglycemic episodes that were severe or confirmed by blood glucose concentration <56 mg/dL.

Results reported from the study showed that oral semaglutide appears to be superior to placebo in decreasing HbA1C where the mean changes from baseline to week 26 for HbA1C were -1.0% for oral semaglutide and -0.2% for placebo for the participants enrolled with type 2 diabetes and moderate renal impairment. Additionally, oral semaglutide was also superior to placebo in decreasing bodyweight where the mean change from baseline to week 26 was -3.4kg for oral semaglutide and -0.9kg for placebo. These results were both statistically significant. In addition to that, 58% of participants in the oral semaglutide group have met the target of HbA1C <7.0% at week 26. The most frequent adverse events reported were mild-to-moderate gastrointestinal events, mainly nausea with a higher proportion of adverse events occurring in the semaglutide group (74%) than with placebo (65%) with a similar proportion reporting serious adverse events (10% vs 11%), and overall renal function remained unchanged in both groups throughout the trial period.

Oral semaglutide is the first oral GLP-1 receptor agonist, and appears to be safe for patients with chronic kidney disease; and, once available, might be preferred by some patients that don’t favor injections. GLP-1 receptor agonists provide better glycemic control and weight loss than regimens containing insulin. Furthermore, the results of the trial were achieved with few hypoglycemic episodes and the drug appears to have acceptable safety and tolerability in most patients. The authors mentioned that one potential limitation of this trial is that the efficacy and safety of oral semaglutide in patients with moderate renal impairment was compared to placebo and not an active comparator. 

In conclusion, oral once-daily semaglutide 14mg was superior to placebo in terms of decreasing HbA1C and body weight in patients with type 2 diabetes and moderate renal impairment while maintaining a consistent safety profile seen for other GLP-1 agonists and fewer hypoglycemic events.

Practice Pearls:

• Oral semaglutide was superior to placebo in decreasing HbA1C and bodyweight at 26 weeks in patients with type 2 diabetes and moderate renal impairment. Renal function remained unchanged in both groups.
• Severe adverse effects reported were almost the same in both groups but a higher proportion of adverse effects in general occurred in the oral semaglutide group (74% vs 65%) with the majority gastrointestinal adverse events.
• Oral semaglutide, once available, will be a good alternative to subcutaneous glucose-lowering medications (such as Liraglutide) for patients with type 2 diabetes and moderate renal impairment.

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 Endocrinol. 2019 Jul;7(7):515-527. doi: 10.1016/S2213-8587(19)30192-5. Epub 2019 Jun 9.

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:

Granhall C, Søndergaard FL, Thomsen M, and Anderson TW: Pharmacokinetics, safety and tolerability of oral semaglutide in subjects with renal impairment. Clin Pharmacokinet 2018; 57: pp. 1571-1580

Marian Ayad, BSPharm, BCPS, PharmD candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences