Burlington and Toronto, Ontario, June 27, 2011 – Boehringer Ingelheim and Lilly today announced Phase III study results for linagliptin, demonstrating improved glycemic control in adults with type 2 diabetes (T2D) whose blood glucose is not adequately controlled on current therapy. In one long-term study over two years evaluating linagliptin or glimepiride when added to metformin, linagliptin was effective at lowering blood glucose, as measured by haemoglobin A1C (A1C)** but with relative weight loss (-1.4 kg vs. +1.5 kg; adjusted mean difference, -2.9 kg; p< 0.0001), reduced incidence of hypoglycaemia (7.5 per cent vs. 36.1 per cent; p< 0.0001) and few cardiovascular (CV) events (1.5 per cent vs. 3.4 per cent; Relative Risk 0.46 [0.23-0.91] p=0.02).1 Results will be presented at the 71st Annual American Diabetes Association (ADA) Scientific Sessions in San Diego, California from June 25 - 29, 2011.
"The combination of linagliptin plus metformin provides meaningful glucose control comparable to that of a combination of a sulphonylurea plus metformin. The added benefit is that, linagliptin is not associated with weight gain and does not per se increase the occurrence of hypoglycaemia" said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "In addition, linagliptin was associated with a 54 per cent relative risk reduction for cardiovascular events in this study. This highlights the promising cardiovascular safety data seen with linagliptin to date which we are currently further exploring in the CAROLINA study."
Another study of 24-weeks duration evaluating linagliptin demonstrated mean placebo-corrected A1C reductions of up to 1.7 per cent from baseline when linagliptin 2.5 mg twice daily (bid) was used in combination with metformin 1,000 mg bid in T2D patients with insufficient glycemic control.2 The combination of linagliptin plus metformin was well tolerated and improved glycemic control more than either medication when used alone. In the trial, there was no weight gain with the linagliptin plus metformin combination, and a very low risk of hypoglycaemia (five cases, or 1.8 per cent of patients).2 In an open label arm including patients with poor glycemic control (A1C at baseline >11 per cent) linagliptin 2.5 mg twice daily (bid) in combination with metformin 1,000 mg bid achieved a reduction from baseline of A1C of 3.7 per cent.2
Linagliptin was also evaluated in T2D patients with varying degrees of renal function.3 A large pooled analysis of three randomised, placebo-controlled Phase III trials (n=2,141) showed that patients who received linagliptin had A1C reductions independent of their degree of renal function, with placebo corrected mean -0.63 per cent (p< 0.0001) for those with normal renal function and -0.69 per cent for those with mildly or moderately impaired renal function (p< 0.0001, p=0.0174, respectively).3 In an additional study evaluating T2D patients with severe renal impairment (RI) whose blood glucose was insufficiently controlled, linagliptin provided placebo-corrected A1C reduction of -0.6 per cent (p< 0.0001) after 12 weeks of treatment.4 Renal function remained stable over time and CV deaths in this high-risk population were low: one patient per arm.4
About the Linagliptin Studies
Two year phase III study comparing linagliptin to glimepiride, add on to metformin (39-LB)1
The aim of this two-year study was to assess the long-term efficacy and safety profile of adding linagliptin or glimepiride to ongoing stable metformin (greater than or equal to 1,500 mg/d for greater than or equal to 10 weeks) to treat T2D in those who have not achieved glycemic control.
- T2DM patients on stable metformin (1,500mg/d) for 10 weeks were randomised to linagliptin 5mg/d (N=764) or glimepiride 1−4 mg/d (N=755) over two years.The efficacy endpoint was the change in A1C from baseline. Key secondary endpoints assessed the frequency of hypoglycemic events and changes in body weight over time. Another safety endpoint evaluated pre-specified, prospective and adjudicated capture of CV events.
Combination with Metformin in T2D Patients (279-OR)2
The aim of this 24-week, study was to evaluate the combination of linagliptin plus metformin in T2D patients with inadequate glycemic control.
- The six treatment groups were randomised into combinations of linagliptin 2.5 mg bid plus either low- or high-dose (500 or 1000 mg) metformin bid, linagliptin 5 mg once daily (qd), metformin 500 or 1,000 mg bid, and placebo. Patients with a baseline A1C greater than or equal to 11 per cent received open-label combination therapy with linagliptin 2.5 mg plus metformin 1,000 mg bid (n=66). Mean baseline A1C was between 8.5 per cent and 8.7 per cent, and 11.8 per cent in the open-label arm. Adverse event (AE) rates were similar across treatment arms.
Efficacy and Safety in Patients with T2D with or Without RI (1068-P)3
The aim of this pooled analysis of three global studies was to evaluate the effect of renal function on the efficacy and safety of linagliptin in T2D patients with or without declining renal function.
- The primary endpoint in all trials was the change in A1C from baseline to week 24. The data assessed 2,141 patients with T2D who were grouped by renal function as normal GFR greater than or equal to 80 mL/min, n=1,684), mild RI (GFR, 50 to less than 80 mL/min, n=418), or moderate RI (GFR, 30 to less than 50 mL/min, n=39).
- Patients who received linagliptin showed consistent placebo-corrected adjusted mean A1C changes across all three groups (-0.6 per cent in both the normal and mild RI groups and -0.7 per cent in the moderate RI group).
- The proportion of patients reporting a severe AE with linagliptin in the normal/mild/moderate groups were 2.5 per cent, 5.4 per cent and 3.7 per cent, respectively; and placebo was 3.4 per cent, 3.8 per cent, 8.3 per cent, respectively.
- Renal function, as assessed by Glomerular Filtration Rate (GFR), and the urinary albumin/creatinine ratio (a surrogate for diabetic nephropathy), was unaffected in all three groups after 24 weeks of linagliptin treatment.
Safety and Efficacy in T2D Patients with Severe RI (413-PP)4
The aim of this study was to evaluate the effect of renal function on the efficacy and safety of linagliptin in T2D patients (defined as A1C greater than or equal to 7 per cent and less than or equal to 10 per cent) and severe RI (defined as GFR less than 30 mL/min/1.73 m2).
- The primary endpoint was the change in A1C from baseline to week 12. The study assessed linagliptin 5 mg qd (n=68) vs. placebo (n=65) in patients whose glucose-lowering background therapy remained unchanged (insulin and/or sulphonylurea).
- The change from baseline for all patients with linagliptin tablets 5 qd was -0.8 per cent (n=66) and with placebo -0.2 per cent (n=62) p= 0.0001. The change from baseline in the subgroup of poorly controlled patients (baseline A1C greater than or equal to 9 per cent) was -1.5 per cent with linagliptin 5 qd (n=11) and -0.3 per cent with placebo (n=13), p= 0.0021.
- The proportion of patients reporting an AE was 85.3 per cent for linagliptin and 70.8 per cent for placebo, respectively. Hypoglycaemia occurred in 51.5 per cent of linagliptin and 27.7 per cent of placebo-treated patients. Notably, 61 of the 66 patients receiving linagliptin were on their unchanged doses of insulin and/or sulphonylurea background therapy. Renal function remained stable throughout the study in both treatment arms and CV deaths in this high-risk population were low: one patient per arm.
Source: New data for linagliptin to be presented at the ADA