Diabetes Drug Works Despite Renal Damage

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SAN DIEGO—Linagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, appears to be a good treatment option for patients with type 2 diabetes and severe renal impairment, researchers announced at the 71st Scientific Sessions of the American Diabetes Association.

The results, from a 12-week study, showed that linagliptin was associated with “clinically meaningful” improvements over placebo in glycemic control without notable side effects in diabetic patients with inadequately controlled hyperglycemia with severely compromised renal function.

“While declining renal function is a frequent complication of type 2 diabetes, the management of type 2 patients with renal impairment may be difficult,” said Lance Sloan, MD, a nephrologist and endocrinologist who is President and Chief Medical Officer of the Texas Institute for Kidney and Endocrine Disorders in Lufkin. “Several oral antidiabetic drugs such as metformin should not be used because of safety and tolerability concerns while other antidiabetic drugs may produce fluid retention or hypoglycemia.”

“DPP-4 inhibitors are relatively new antidiabetic drugs, and doctors tend to consider this class of agents suitable for use in patients with diabetes ‘earlier on'….before they have developed cardiorenal problems,” he added. “There's always been concern—especially because of a lack of data—about how effective these drugs are in diabetic patients with severe renal impairment. Do they have less efficacy or no efficacy and are we wasting money by even trying these agents in this group of patients and, more importantly, perhaps increasing their risk of complications with no real benefit? So it's important to have data to know whether patients with severe renal impairment can benefit from linagliptin.”

Currently available DPP-4 inhibitors undergo extensive renal clearance and either require dose adjustment or are not recommended for use in patients with moderate or severe declines in renal function. Linagliptin is the first approved once-daily DPP4-inhibitor that is primarily excreted mostly in the gastrointestinal tract via bile and gut, with only about 5% of the drug excreted via the kidneys. The agent can therefore be used in patients with declining renal function without the need for dose adjustment.

“Physicians—non-kidney specialists or family physicians—may prescribe a DPP4-inhibitor and forget to check the patient's renal function to begin with  or fail to monitor kidney function that's declining because of  the patient's diabetes or hypertension or other medical condition,” Dr. Sloan said. “So this means that a drug that should be adjusted may not get adjusted. With linagliptin, no dosage adjustment is needed so it makes it easier and safer to use.”

For the study, the investigators randomized 133 patients to 12 weeks' treatment with either linagliptin 5 mg once daily or placebo plus their usual antidiabetic background therapy which included insulin, sulfonylurea, and/or other antidiabetic drugs.

The two treatment groups were similar with respect to demographics, metabolic parameters, and their glucose-lowering regimen.

Participants had a hemoglobin A1c (HbA1c) of 7%-10.0% and severe renal impairment, defined as a glomerular filtration rate (GFR) below 30 mL/min/1.73 m2. The primary endpoint was the change from baseline in HbA1c after 12 weeks of treatment.

Results showed that Hba1C decreased by 0.76 percentage points in linagliptin and 0.18 percentage points in placebo patients for the entire group.

In patients who were poorly controlled (defined as having an HbA1C of 9.0% or higher), HbA1C decreased by 1.46 percentage points from baseline in linagliptin patients and 0.28 percentage points from baseline in placebo patients.

Renal parameters and blood potassium levels remained unchanged with linagliptin.

Linaglipin-treated patients were more likely to develop hypoglycemia than placebo-treated patients however it was usually asymptomatic and mild.

“These are very complex patients who are at high risk of cardiorenal disease because they have diabetes, a major risk factor for cardiac and renal problems,” Dr. Sloan said.  “And they already have kidney disease, which increases their risk of cardiovascular death even more than diabetes. These patients are on multiple medications for multiple problems, and so it's nice to be able to put them on an antiglycemic medication without worrying about needing to adjust the dosage with the expected decline in renal function.”
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