PIONEER trials test oral semaglutide in moderate renal impairment, flexible dosing
medwireNews: The PIONEER 5 and 7 trials show the efficacy of oral semaglutide in people with moderate renal impairment and the potential for a flexible dosing regimen.
Both trials were presented this week at the 79th ADA Scientific Sessions in San Francisco, California, USA, with simultaneous publication in The Lancet Diabetes & Endocrinology.
PIONEER 5 involved 324 patients with type 2 diabetes who were taking metformin with or without a sulfonylurea or basal insulin and had an estimated glomerular filtration rate of 30–59 mL/min per 1.73 m².
During 26 weeks of treatment, those taking oral semaglutide (dose escalated to 14 mg/day) had a significant 1.0 percentage point reduction in glycated hemoglobin (HbA1c), which was significantly greater than the 0.2 percentage point reduction seen in those taking placebo.
Renal function was generally unchanged in both groups throughout the treatment period, report Ofri Mosenzon (Hadassah Hebrew University Hospital, Jerusalem, Israel) and co-researchers. Gastrointestinal side effects were the most frequent complaint, were significantly more common in the semaglutide than placebo group, and were the most common reason for discontinuing treatment, which occurred in 15% of the semaglutide group versus 5% of the placebo group.
In a linked commentary, Michael Nauck and Juris Meier, both from Ruhr-University Bochum in Germany, say: “Given the suitability of only a few classes of oral glucose-lowering drugs for the treatment of type 2 diabetes in those with chronic kidney disease, this study is highly relevant and helpful for a relatively large subpopulation of patients with both type 2 diabetes and chronic kidney disease.”
PIONEER 7, from Thomas Pieber (Medical University of Graz, Austria) and colleagues, is similar to the previously published PIONEER 3, testing three doses of oral semaglutide against the dipeptidyl peptidase-4 inhibitor sitagliptin. But whereas the three doses in PIONEER 3 were fixed, the PIONEER 7 investigators adopted a flexible dosing approach, in a bid to identify the maximum tolerated dose for individual patients.
By 52 weeks, 9% of the 253 patients assigned to semaglutide were using the 3 mg dose, with 30% and 59% using the 7 and 14 mg doses, respectively. The proportion of people achieving the HbA1c target of 7.0% (53 mmol/mol) at this point was 58% of 230 patients in the semaglutide group, which was a significant improvement on the 25% achieved by 238 patients given sitagliptin.
Semaglutide-treated patients achieved average HbA1c levels that were a significant 0.5 percentage points lower than those achieved by the sitagliptin group, and the treatment difference for bodyweight was an average 1.9 kg in favor of semaglutide treatment.
However, despite the flexible dosing regimen, Nauck and Meier observe that the results were similar to those of PIONEER 3, suggesting that the approach “has not entirely fulfilled expectations of an individually optimised dose leading to better effectiveness while avoiding side-effects and, foremost, drug discontinuation.”
Nine percent of patients discontinued semaglutide because of adverse events, compared with 3% who discontinued sitagliptin.
“Interestingly, most of [the] side-effects and drug discontinuations occurred in the first 8 weeks, when all participants randomly assigned to oral semaglutide took 3 mg per day per protocol,” say Nauck and Meier.
They call for more research into flexible dosing regimens using both higher and lower doses than used in this study, to further reduce discontinuations and make use of even higher doses in patients who can tolerate them, noting that these are already used to treat obesity.
“[T]he one-size-fits-all approach that has been used traditionally in the [glucagon-like peptide-1] receptor agonist field could now be challenged,” they conclude.
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Lancet Diabetes Endocrinol 2019; doi:10.1016/S2213-8587(19)30192-5 (PIONEER 5)
Lancet Diabetes Endocrinol 2019; doi:10.1016/S2213-8587(19)30194-9 (PIONEER 7)
Lancet Diabetes Endocrinol 2019; doi:10.1016/S2213-8587(19)30182-2 (commentary)
79th ADA Scientific Sessions; San Francisco, California, USA: 7–11 June 2019