Four studies find linagliptin effective as monotherapy, add-on in adults with type 2 diabetes

Linagliptin administered alone or in combination with other diabetes medications, and as an add-on to basal insulin therapy, lowered HbA1c in elderly patients with diabetes and in adults with type 2 diabetes and diabetic nephropathy. Additional data suggest that linagliptin improved blood glucose control without putting patients at additional risk for hypoglycemia or weight gain.

The new findings on linagliptin (Tradjenta, Boehringer Ingelheim Pharmaceuticals Inc., Eli Lilly and Company) were presented during a tele-briefing at the European Association for the Study of Diabetes 48th Annual Meeting in Berlin.

Add-on therapy

In one study, researchers examined 1,261 patients who had inadequate glucose control, and were taking insulin glargine, insulin detemir or neutral protamine Hagedorn (NPH) insulin. They were randomly assigned to linagliptin 5 mg daily or placebo in a 1:1 fashion for at least 52 weeks. According to researchers, the dose of basal insulin was kept stable for 24 weeks and was adjusted thereafter.

The mean age for the linagliptin group was 59.7 years, with a BMI of 30.8, HbA1c of 8.3% and basal insulin dose of 42 IU per day. The placebo group was similar, with a mean age of 60.4 years, a BMI of 31.2, HbA1c of 8.3% and a basal insulin dose of 40 IU per day.

According to data, exposure to the study medication went beyond 52 weeks and was comparable in both groups (linagliptin, 435 days; placebo, 422 days). The number of patients with more than one adverse event was lower with linagliptin (78.4%) compared with placebo (81.4%). Moreover, most adverse events were mild or moderate, data indicate.

The researchers found that incidence of hypoglycemia was similar in both groups (31.4% in linagliptin and 32.9% in placebo) and changes in body weight were minimal (linagliptin, –0.3 kg; placebo, –0.04 kg).

At week 52, researchers discovered the placebo-adjusted mean change in HbA1c from baseline for linagliptin was –0.53% (P<.0001), followed by an increased mean change in basal insulin dose of 2.6 IU per day for linagliptin vs. an increase of 4.2 IU per day for placebo (P<.003).

Thus, the addition of linagliptin to basal insulin therapy among patients with type 2 diabetes who had inadequately controlled glycemic measures significantly improved their long-term glycemic control during a period of 52 weeks. This resulted in no added risk for hypoglycemia or weight gain.

Monotherapy or add-on therapy

In a second study presented during a tele-briefing, data demonstrated that linagliptin lowered albuminuria in patients with type 2 diabetes and early nephropathy beyond the expectations of researchers.

Seven double blind, placebo-controlled, randomized trials of linagliptin as a single therapy or as an add-on therapy to various glucose-lowering therapies were conducted for 24 to 52 weeks. All studies had available data to create urinary albumin-to-creatinine ratios (UACR) for the study (n=4,113).

After 24 weeks of treatment, the researchers pooled data into two sets. The first set of data included patients from four 24-week pivotal phase 3 trials, who had persistent albuminuria and stable treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) at baseline. These patients were in the earlier stages of type 2 diabetes with nephropathy (with and without oral glucose-lowering medications).

The second set of data included elderly patients with diabetes and nephropathy (aged ≥65 years), taking several glucose-lowering medications, including insulin. These patients came from all seven trials with UACR criteria.

According to data, of patients in the first set, 492 (out of 2,472 patients) met UACR criteria and 46% received stable ACE inhibitor/ARB therapy (linagliptin, n=168; placebo, n=59). Of patients in the second set, 1,331 patients were aged ≥65 years and 377 (28%) met UACR criteria (linagliptin, n=232; placebo, n=145).

Additional data indicate linagliptin lowered adjusted UACR by 33% (95% CI, 22-44; P<.05). The researchers found that out of all seven studies, BP and renal function were not significantly affected.

Elderly population

In a third study presented, researchers demonstrated that linigliptin also resulted in clinically meaningful improvements in glycemic control without an excessive risk for hypoglycemia in patients aged 70 years or older.

Using two phase 3 studies evaluating linagliptin vs. placebo as an add-on to basal insulin, researchers examined the efficacy, safety and tolerability in patients aged 70 years or older (n=247). Patients were inadequately controlled on insulin glargine, insulin detemir or NPH insulin, and received linagliptin 5 mg once daily (n=126) or placebo (n=121).

“In this study, linagliptin achieved significant reductions in HbA1c of –0.77% (placebo-adjusted change in HbA1c from baseline (P<.0001), with a rate of hypoglycemia of 28.6% in linagliptin-treated patients and 37.2% in placebo-treated patients,” Christophe Arbet-Engels, MD, PhD, MBA, vice president of metabolic-clinical development and medical affairs at Boehringer Ingelheim, said during the tele-briefing.

According to data, at week 24, placebo-adjusted mean change in HbA1c with linagliptin was –0.77%; (95% CI, –0.95 to –0.59; P<0.0001).

“In this population, the overall incidence of adverse events for linagliptin in combination with basal insulin was not higher than placebo,” Arbet-Engels said.

Arbet-Engels added that linagliptin used in combination with basal insulin in elderly patients aged 70 years or older was well-tolerated and allowed for clinically significant improvements in glycemic control, without an excessive risk for hypoglycemia.

No dose adjustments needed

Researchers presented a fourth study on the post-hoc data (n=1,331) from phase 3 trials of linagliptin 5 mg once daily as monotherapy or add-on therapy for at least 24 weeks.

Patients were assigned linagliptin (n=841) or placebo (n=490). Of these, 21% had a diabetes duration of >5 years and more than 60% of patients were receiving more than two glucose-lowering medications.

According to data, there was a significantly greater reduction in fasting plasma glucose from baseline to week 24 in patients taking linagliptin (placebo-adjusted mean change=–14.8 mg/dL; 95% CI, –20.7 to –8.9; P<.0001). Approximately 71.3% of patients who received linagliptin and 73.3% of patients who received placebo had adverse events. However, drug-related adverse events were less common in patients taking linagliptin (18.1%) compared with placebo (19.8%), data indicate.

Moreover, the incidence of hypoglycemia was lower in patients who were given linagliptin (21.4%) compared with placebo (25.7%). The researchers report that at least one adjudicated cardiovascular event occurred among 0.8% of linagliptin patients and 1% of placebo-treated patients.

The researchers said linagliptin is well-tolerated and an efficacious treatment option for elderly patients with type 2 diabetes, without a dose adjustment.

For more information:

Groop P-H. OP36.

Patel S. P850.

Woerle H-J. P848.

Yki-Järvinen H. OP6.

All presented at: the European Association for the Study of Diabetes 48th Annual Meeting; October 1-5, 2012; Berlin.

Disclosures: All studies were funded by Boehringer Ingelheim and Eli Lilly and Company.