LISBON – in a 16-week, dose-ranging, phase 2 trial performed in patients with type 2 diabetes mellitus and chronic kidney disease (CKD).
There was also a reduced incidence of gastrointestinal side effects with metformin DR versus immediate-release (IR) metformin (less than 16% at all doses tested vs. 28%), particularly with regard to nausea (1%-3% vs. 10%).
Sara Freeman/Frontline Medical News
Dr. Juan Pablo Frias
“Based on concerns about the potential for lactic acidosis, primarily in patients with fairly severe renal impairment, metformin use is contraindicated in patients with stage IV chronic kidney disease,” Dr. Frias observed. Furthermore its use is restricted in patients with stage IIIB CKD, with European guidelines recommending lower starting (500 mg) and maximum (1,000 mg) daily doses, and U.S. guidelines recommending continuing treatment with caution in those already on metformin and not initiating metformin in new patients with this stage of kidney disease.
Treating patients with type 2 diabetes mellitus (T2DM) and later stages of CKD is challenging, as there are issues with almost all of the available alternatives to metformin, he noted. For instance, insulin use and sulfonylureas carry the risk of hypoglycemia, which is higher in patients with stage IIIB/IV renal disease than without. The dipeptidyl peptidase-4 inhibitors are “modestly able to reduce A1c, but generally do much better in combination with metformin, which is often contraindicated in these patients,” Dr. Frias said. Sodium glucose cotransporter 2 inhibitors are “generally not effective” in this patient group, he said.
Metformin DR is being specifically developed to manage patients with T2DM patients and stage IIIB/IV CKD, Dr. Frias said. Its enteric coating helps it bypass the stomach and upper intestine and so ensures that the majority of metformin absorption occurs in the lower bowel to reduce systemic exposure while retaining its positive effects on glycemic mechanisms such as the secretion of glucagon-like peptide 1.
In the current phase 2 study, 571 patients with T2DM and stage I/II CKD were recruited. Patients with stage IIIB/IV were not included because of the restrictions on the use of metformin.
Patients were randomized to receive placebo or metformin DR (600 mg, 900 mg, 1,200 mg, and 1,500 mg twice daily) in a double-blind comparison, with a single-blind reference arm of metformin IR, (1,000 mg once daily for the first week then 1,000 mg twice daily) also included as part of the study design.
The change in hemoglobin A1c (HbA1c) from baseline levels to week 16 of treatment, the primary endpoint, was significantly (P less than .05) greater with metformin DR) than with placebo (–0.49%, –0.62%, and –0.06%, respectively). Changes in fasting plasma glucose (FPG) from week 4 to week 16 were also higher with metformin DR than with placebo, with the 1,200 metformin DR dose achieving a 25.1 mg/dL drop in FPG, “almost 80% of the fasting glucose–lowering capacity of the immediate release formulation.”
While the changes in HbA1c (-1.10%) and FPG (-32.6 m/dL) were greatest with metformin IR, the lower systemic exposure needs to be considered, Dr. Frias said. The plasma exposure with metformin DR was less than 37% that of metformin IR.
“If we normalize for systemic exposure, so for any given unit, if you will, of systemic exposure, you actually had [a 1.5-fold] improved hemoglobin A1c with the delayed-release formulation, and a twofold increase in the fasting glucose,” Dr. Frias reported. “So from a practical point of view, if you needed to reach those ‘safe’ plasma concentrations with an immediate-release formulation, you would have to lower [the dose of] that formulation, probably to a dose that would not be efficacious for a patient.”
As for safety, any adverse event (AE) occurred in 41.7% of placebo-treated patients, in 47.9% of metformin IR–treated patients, and in 55.3%, 48.4%, 39.6%, and 43.8%, of those taking metformin DR at the respective doses of 600 mg, 900 mg, 1,200 mg, and 1, 500 mg.
Serious AEs were recorded in 4.2% of placebo-treated patients, 1.1% of metformin IR-treated patients, and in 1.1%, 0%, 4.2%, and 1.0% those taking increasing doses of metformin DR.
There were fewer AEs related to study medication (12.8%, 13.7%, 14.6%, and 9.4%) and subsequently resulting in discontinuation (3.2%, 2.1%, 7.3%, 2.1%) with metformin DR than with metformin IR (25.5%, 8.5%). Of placebo-treated patients, 6.3% developed a treatment-related AE, and 6.3% discontinued the study as a result.
“The improved risk/benefit profile that’s seen [in this study] would lead you to think that this would be a formulation that would be effective, particularly in patients with CKD IIIB or IV,” Dr. Frias concluded, noting that further studies would need to look into this possibility further.
The study was funded by Elcelyx Therapeutics. Dr. Frias disclosed receiving research support from Abbvie, Eli Lilly, IONIS, Janssen, Johnson & Johnson, Merck, Mylan, Novartis, Pfizer, and vTv therapeutics. He has also received research support from and participated in scientific advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, and Theracos. A coauthor is an employee of Elcelyx Therapeutics and disclosed being a shareholder of the company.