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ADA: New and Novel DPP-4 Reduces HbA1c Alone and in Combination

A novel dipeptidyl peptidase 4 (DPP-4) inhibitor — linagliptin — showed improved glycemic control as monotherapy, as an add-on, and in combination with other oral diabetes medications, researchers reported…. 

In four phase-III trials, linagliptin significantly improved HbA1c alone, as an add-on to metformin or metformin plus a sulfonylurea, and in combination with pioglitazone (Actos), according to four posters presented at the ADA meeting. However, hypoglycemia appeared to be a concern in both the metformin-plus-sulfonylurea and the pioglitazone groups.

Giora Davidai, MD, director of medical affairs for Boehringer Ingelheim stated that, “Linagliptin is a very viable alternative for the treatment of diabetes.” He added that linagliptin appears to have a primarily non-renal route of excretion, which may bode well for the large numbers of diabetes patients who do have renal problems. “Only 5% is cleared by the kidney,” he said. “All the rest is cleared by other means.”

Researchers presented the results of four 24-week, randomized, double-blind, placebo-controlled trials of linagliptin during an ADA poster session.

In the linagliptin-as-monotherapy trial, 503 patients were randomized to 5 mg daily of the drug or placebo. At the end of the study, those on the drug had a 0.69% greater reduction in HbA1c from baseline compared with those on placebo (P<0.0001), and more patients on linagliptin achieved an HbA1c reduction of 0.5% or greater (47.1% versus 19%).

There were also greater reductions in fasting plasma glucose (-23.3 mg/dL) and postprandial glucose (-58.4 mg/dL) for linagliptin compared with placebo (P<0.0001), as well as improved insulin secretion (P<0.05).

Adverse events were the same in both groups, and hypoglycemia was rare.

In another trial, 601 patients were randomized to linagliptin or placebo as an add-on to metformin.

The researchers found a significantly greater reduction in HbA1c in the active drug group compared with placebo (-0.64%, P<0.0001).

Patients on the drug combo had significantly better improvements in fasting plasma glucose and postprandial glucose as well. Adverse events were comparable and hypoglycemia was rare.

In a third trial, 1,058 patients were randomized to either linagliptin as an add-on to both metformin and a sulfonylurea, or a placebo add-on.

The researchers found a significantly greater reduction in HbA1c among those in the drug group compared with the placebo group (-0.62%, P<0.0001), and they also had a greater likelihood of achieving an HbA1c of 7% (OR 5.5, P<0.0001).

The linagliptin patients also had better fasting plasma glucose and improvements in beta-cell function (P<0.005), but the trial didn't assess postprandial glucose.

Still, the researchers cautioned that there was significantly more hypoglycemia in the drug group (22.7% versus 14.8%), warning that “when linagliptin is added on to preexisting sulfonylurea therapy, hypoglycemia may occur.” More hypoglycemic events were also seen when patients took linagliptin in combination with pioglitazone, compared with a placebo in combination with the thiazolidinedione.

Among 389 patients, there were three episodes of hypoglycemia (1.2%) in the drug group, compared with none in the placebo plus pioglitazone group.

Those in the linagliptin combination group had greater improvements in HbA1c (-0.51%, P<0.001) and were twice as likely to achieve an HbA1c target of 7% (OR 2.1, P<0.0051).

Davidai said the researchers “still have a lot of work to do,” including assessing weight loss or gain, but the company plans to file a new drug application “in the near future.”

Practice Pearls:
  • Explain that a novel DPP-4 inhibitor — linagliptin — appears to improve glycemic control alone, as an add-on, and in combination with a thiazolidinedione.
  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Del Prato S, et al “Linagliptin monotherapy improves glycemic control and measures of beta-cell function in Type 2 diabetes” ADA 2010; Abstract 695-P.
Taskinen MR, et al “Efficacy and safety of linagliptin in Type 2 diabetes patients inadequately controlled on metformin monotherapy” ADA 2010; Abstract 579-P.
Owens DR, et al “Linagliptin improves glycemic control in Type 2 diabetes patients inadequately controlled by metformin and sulfonylurea without weight gain and low risk of hypoglycemia” ADA 2010; Abstract 548-P.

Gromis R, et al “Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled Type 2 diabetes” ADA 2010; Abstract 551-P.