American Diabetes Association (ADA) 72nd Scientific Sessions: Page 2 of 3

August 16, 2012

Dapagliflozin Added to Sitagliptin Reduces Glycated Hemoglobin Levels

After 48 weeks of treatment, patients with type 2 diabetes who took dapagliflozin had significant reductions in hemoglobin A1c (HbA1c) compared with placebo as an add-on therapy to sitagliptin, according to a phase 3, multicenter, randomized, double-blind, placebo-controlled study. Results were presented in an ADA poster session.

Dapagliflozin is an oral selective sodium-glucose cotransporter 2 inhibitor. In January 2012, the US Food and Drug Administration (FDA) told the drug’s manufacturers (Bristol-Myers Squibb and AstraZeneca) that it needed more data before making a decision on its approval. In July 2011, an FDA advisory committee recommended that the drug not be approved, citing potential risks of breast and bladder cancer.

In this study, 447 adults were randomized in a 1:1 ratio to receive 10 mg per day of dapagliflozin (n=223) or placebo (n=224) plus 100 mg per day of sitagliptin with metformin or without metformin. The patients all had type 2 diabetes and were inadequately controlled by sitagliptin or sitagliptin plus placebo. They also had an HbA1c between 7.0% and 10.0%. The study included a 24-week treatment period followed by a 24-week extension.

At 24 weeks, patients in the dapagliflozin plus sitagliptin with or without metformin group had a 0.48% decrease in HbA1c from baseline compared with patients who took placebo plus sitagliptin with or without metformin (P<.0001). There was a greater effect in dapagliflozin added to sitagliptin compared with placebo added to sitagliptin (HbA1c reduction of 0.56%; P<.0001). However, there was still a significant decrease of 0.40% when dapagliflozin was added to sitagliptin and metformin compared with placebo plus sitagliptin with metformin (P<.0001). The authors noted that the results remained consistent during the 24-week extension period.

After 48 weeks, 66.2% of patients taking dapagliflozin and 61.1% of patients taking placebo had more adverse events. The rates for more than one serious adverse event were also similar (6.7% vs 8.0%, respectively). Hypoglycemia was found in 5.3% of dapagliflozin patients and 6.2% of placebo patients.—Tim Casey


Linagliptin Reduces Marker of Kidney Function Decline in Patients With Diabetes

Linagliptin (Tradjenta), an oral agent approved to treat type 2 diabetes mellitus (T2DM), reduced urinary albumin-to-creatinine ratios (UACRs) significantly over 24 weeks in patients with diabetic nephropathy, according to a study presented at the ADA meeting. Elevated albumin levels in the urine, or albuminuria, indicates worsening kidney and cardiac function in patients with T2DM. Diabetes is a leading cause of kidney failure, and investigators said that linagliptin’s ability to reduce albuminuria in patients suggests it has kidney-protective properties.

In conducting the post-hoc analysis, researchers identified a subset of 227 patients from four phase 3 trials who had diabetic nephropathy at enrollment and were regularly taking an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) to slow the progression of renal impairment. The study included men and women primarily of white (70%) and Asian (26%) descent.

Patients were randomly assigned to 5 mg of linagliptin daily with or without another glucose-control agent (n=168) or to placebo (n=59) for 24 weeks. Patient and disease characteristics were well balanced between the cohorts, and the groups had similar proportions of patients with microalbuminuria and macroalbuminuria. Slightly more patients in the linagliptin group than in the placebo group had mild to moderate renal impairment at baseline (normal renal function, 47.0% vs 57.6%, respectively).

At 24 weeks, linagliptin was associated with a 33% reduction in baseline UACR, a difference of 29% compared with placebo (P=.0305). In a sensitivity analysis of data for 249 patients who took part in the trials but were not using ACEs or ARBs, investigators found a median 30% reduction in baseline UACR for patients treated with linagliptin compared with 16% for those given placebo. The effects of linagliptin on UACR were evident within 12 weeks of initiating therapy and were consistent across all racial subgroups.

Linagliptin also lowered patients’ levels of glycated hemoglobin (HbA1C) and fasting plasma glucose at 24 weeks. Investigators found no correlation between degree of improvement in glycemic control and change in UACR, however, with patients whose HbA1C levels declined by <0.1% experiencing a reduction in UACR similar to that for patients whose HbA1C levels dropped by more than 0.64%. They said that this suggests linagliptin “may have kidney-protective properties beyond glucose-lowering effects.”

Patients in the placebo arm experienced a small drop in blood pressure levels, whereas blood pressure levels remained stable in the linagliptin arm. Kidney function was also stable in the linagliptin arm, which had a slightly lower composite rate of renal and urinary disorders at 24 weeks compared with the placebo group (5.1% vs 4.2%, respectively).

The rates of adverse events in the trials were low, overall, with hypoglycemia the only treatment-related adverse event observed in more than 2% of patients taking linagliptin. All 14.3% of patients in the linagliptin arm who experienced hypoglycemia had also been taking a sulfonylurea; none required medical assistance.

In a press release by the drug’s manufacturer, lead investigator Per-Henrik Groop, MD, DMSc, Division of Nephrology, Helsinki University Central Hospital, Finland, said, “This analysis is important because approximately 65% of patients living with T2DM are at risk of declining renal function, which can limit treatment options.” He added that, based on the results of the post hoc analysis, the research team planned to study the relationship between linagliptin and urine albumin levels further. “We recognize the importance of considering declining renal function when treating T2DM patients,” he said.

Diabetes-related kidney disease can progress even in patients with good glucose control. To monitor the risk of renal impairment in patients with T2DM, the ADA and the National Institutes of Health recommend testing urine albumin excretion levels and estimated glomerular filtration rate annually.—Garrett Melton