SAN FRANCISCO — In patients with both type 2 diabetes and moderate chronic kidney disease (CKD), the investigational oral glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (Novo Nordisk) lowered HbA1c by 1% over 26 weeks.
The patients — who were also receiving metformin, sulfonylurea, or insulin, or a combination of one of the latter two with metformin at baseline and throughout the study — also lost about 3.7 kg by the end of treatment.
About 10% of patients had various gastrointestinal adverse events, however.
Ofri Mosenzon, MD, Hebrew University Hospital, Jerusalem, Israel, presented the results from PIONEER 5, a phase 3a randomized controlled trial, in a poster at the American Diabetes Association (ADA) 2019 Scientific Sessions on June 9. The study was simultaneously published online in Lancet Diabetes & Endocrinology.
Mosenzon and colleagues conclude that "Once daily oral semaglutide 14 mg... appears to provide an important addition to the currently suboptimal treatment options for patients with type 2 diabetes and moderate renal impairment."
The reduction in HbA1c is meaningful, Mosenzon said at the poster session, considering that these patients were already receiving, and continued to receive, other glucose-lowering agents.
"We all know this degree of renal dysfunction is causing a lot of problems with their diabetes control," she told Medscape Medical News.
The study showed that this first oral GLP-1 receptor agonist "brings significant improvement in [patient] outcomes with acceptable rates of expected side effects," she added.
The findings "attest to a major advance in the treatment of type 2 diabetes," Michael A. Nauck, MD, and Juris J. Meier, MD, both from Ruhr-University, Bochum, Germany, write in an accompanying editorial.
Specifically, these results show that oral semaglutide "combines the advantages of GLP-1 receptor agonists [of no increased risk of hypoglycemia] with oral administration (which is unique)," Nauck added in an email to Medscape Medical News.
However, although "preservation of kidney function has been shown in trials with subcutaneous liraglutide and dulaglutide (another GLP-1 agonist)," Nauck and Meier note, "the 26-week duration of PIONEER 5 was probably too short for a definite answer on effect on kidney function."
That is, "with an average loss of [estimated glomerular filtration rate (eGFR)] of 2-5 mL/min/year, it takes longer [than 26 weeks] to detect significant slowing" of kidney function, Nauck clarified.
The study authors agree that "further and larger studies are needed to better define the place of oral semaglutide, including any potential renoprotective effect."
Nevertheless, they write, this early work suggests semiglutide "has the potential to expand the treatment options for patients with type 2 diabetes and moderate renal impairment."
The editorialists agree that, "given the suitability of only a few classes of oral glucose-lowering drugs for the treatment of type 2 diabetes in those with CKD, [the current] study is highly relevant and helpful for [this] relatively large subpopulation of patients."
"Challenging" Disease Combination to Treat
Combined type 2 diabetes and CKD is "challenging" to treat, Mosenzon and colleagues explain in their article.
For example, a patient's dose of metformin has to be adjusted when eGFR falls below 60 mL/min/1.73m² and the drug is contraindicated when eGFR drops below 30 mL/min/1.73 m², they note.
Dipeptidyl peptidase-4 (DPP-4) inhibitors can be used in patients with CKD (all stages, except stage 5 for saxagliptin), they add, although these drugs (except for linagliptin) must be given at a decreased dose dependent on the stage of CKD.
Most sodium-glucose cotransporter 2 (SGLT2) inhibitors are not recommended in patients with eGFR < 45 mL/min/1.73m² (although this could change given the recent findings from the landmark CREDENCE study, in which patients with the lowest eGFRs experienced the most benefit, as one expert explains in a viewpoint on Medscape Medical News).
And insulin and sulfonylureas are associated with an increased risk of hypoglycemia and weight gain, especially in patients with CKD.
In contrast, the GLP-1 agonists semaglutide, liraglutide, albiglutide, and dulaglutide do not require dose adjustment in patients with stage 4 or 5 CKD, and some were shown to control blood glucose without worsening renal function (eg, liraglutide was superior to placebo and dulaglutide was as effective as insulin).
However, current GLP-1 agonists are given subcutaneously, which "might not be ideal for some patients," according to the researchers.
Nauck agreed with this assessment and added that "the problem with SGLT2 inhibitors is that they preserve renal function, but their glucose-lowering effect is much reduced with lower eGFR," and most are not currently approved for patients with CKD.
Safety Outcomes, Two Ways to Measure Efficacy
The researchers aimed to determine the efficacy and safety of oral semaglutide versus placebo in patients with type 2 diabetes and moderate renal impairment.
They randomized 324 adults in eight countries who had type 2 diabetes (HbA1c 7%-9.5%) and moderate CKD (eGFR 30-59 mL/min/1.73 m2) and were on stable doses of metformin, sulfonylurea, or insulin, or metformin plus sulfonylurea, or metformin plus insulin, to receive oral semaglutide or placebo for 26 weeks added to current therapy.
The 163 patients in the oral semaglutide group received 3 mg/day for 4 weeks, then 7 mg/day for 4 weeks, and then 14 mg/day for 18 weeks (uptitrated to minimize gastrointestinal adverse effects) taken as a once daily tablet.
Patients in both groups were a mean age of 70 years and 52% were women.
On average, participants weighed a mean 91 kg, had a mean eGFR of 48 mL/min/1.73 m2, had a mean HbA1c of 8%, and had a mean diabetes duration of 14 years.
The main efficacy endpoints were change in HbA1c and weight from baseline to week 26.
Patients with persistent uncontrollable hyperglycemia (fasting plasma glucose > 13.3 mmol/L in weeks 12-16 or > 11.1 mmol/L in weeks 17-26) could receive rescue therapy.
Researchers used two statistical approaches to express the efficacy outcomes.
They determined the "treatment policy estimand" — the effectiveness of the drug versus placebo over 26 weeks, based on data from all randomized patients, including those who received rescue medication or discontinued the study.
The also determined the "trial policy estimand" — the effectiveness of the drug versus placebo over 26 weeks, based on data from all randomized patients, excluding those who received rescue medication or discontinued the study.
Another way of looking at this, Mosenzon said, is that the treatment policy estimand, which is very similar to intention to treat, is "what the payors will be interested in," and is the US Food and Drug Administration's proposed new way for reporting efficacy endpoints.
The other measure, trial product estimand, is "what the physician will be interested in," she added. This measure shows the efficacy "if I give [this patient] this drug and [the patient is] able to tolerate it."
Less Need for Rescue, More Discontinuation
Fewer patients receiving oral semaglutide than placebo required rescue medication to adequately lower their blood glucose (4% vs 10%).
However, more patients taking oral semaglutide than placebo had adverse events (74% vs 65%) and more discontinued treatment because of adverse events (15% vs 5%).
The main adverse events with oral semaglutide were gastrointestinal, including nausea (19% of patients), vomiting (12%), constipation (12%), diarrhea (10%), and dyspepsia (10%).
There were three deaths (one in the semaglutide group and two in the placebo group), but these were not considered treatment related.
The adverse events were similar to "what we see with subcutaneous GLP-1 receptor agonists," Mosenzon noted, and other PIONEER trials of oral semaglutide in patients without CKD.
Greater Glycemic Control, Weight Loss
Treatment with oral semaglutide was associated with greater improvements in efficacy outcomes than placebo, with greater benefits using the trial product estimand than the treatment policy estimand statistical approach.
The patients' eGFR and urine albumin excretion stayed the same over the course of the trial, but this was a short trial, Mosenzon conceded.
Efficacy Outcomes Using Two Statistical Approaches
| Treatment Policy
| Trial Product
|Endpoint at Week 26||Oral semaglutide||Placebo||Oral semaglutide||Placebo|
|Change in HbA1c, %||–1.0||–0.2||–1.1||–0.1|
|Change in weight, kg||–3.4||–0.9||–3.7||–1.1|
|HbA1c < 7%, % of patients||58||23||64||21|
| Weight loss ≥ 5%,
% of patients
|HbA1c < 7%, no hypoglycemia, no weight gain, % of patients||51||17||56||16|
Unsurprising Favorable Risk–Benefit Profile
"Oral semaglutide escalated to 14 mg taken once daily was superior to placebo in decreasing HbA1c and bodyweight in patients with type 2 diabetes and moderate renal impairment who were uncontrolled on metformin, sulfonylureas, or both, or basal insulin with or without metformin," the researchers summarize.
At 26 weeks, more than twice as many patients had an HbA1c < 7.0% in the oral semaglutide group than in the placebo group (58% and 64% vs 22% and 21%, calculated in two different ways).
And they achieved this outcome with a similar overall safety profile seen previously with this drug class, without an adverse effect on renal function.
"Since semaglutide, like most GLP-1 agonists (except exenatide and lixisenatide), is not substantially eliminated through the kidneys," the editorialists write, "the overall conclusion that oral semaglutide has a favorable benefit-to-risk ratio in patients with type 2 diabetes and CKD is in line with expectations."
The study was funded by Novo Nordisk. Mosenzon has reported being a member of advisory boards for Novo Nordisk, Eli Lilly, Sanofi, MSD, Boehringer Ingelheim, and AstraZeneca; having grants paid to her institution from AstraZeneca; receiving a research grant from Novo Nordisk; and being a member of speakers bureaus for AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, MSD, and Boehringer Ingelheim. Nauck has reported being a member of advisory boards or consulting for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, GlaxoSmithKline, Hoffman La Roche, Menarini/Berlin Chemie, MSD, Novo Nordisk, and Versatis; receiving grant support from Eli Lilly, Menarini/Berlin-Chemie, MSD, and Novartis; and serving on speakers bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini/Berlin Chemie, MSD, Novo Nordisk, and Sun Pharma. Meier has reported receiving consulting and speaker honoraria from AstraZeneca, Eli Lilly, MSD, Novo Nordisk, and Sanofi, and receiving research support from Eli Lilly, Boehringer Ingelheim, MSD, Novo Nordisk, Novartis, and Sanofi.
ADA 2019 Scientific Sessions. Presented June 9, 2019. Abstract 1004-P
Lancet Diabetes Endocrinol. 2019;7:515-527, P500-502. Abstract, Editorial
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Cite this: PIONEER 5: Oral Semaglutide for Diabetes With Moderate CKD - Medscape - Jun 24, 2019.