Effects of Adding Linagliptin to Basal Insulin Regimen for Inadequately Controlled Type 2 Diabetes

Abstract

OBJECTIVETo evaluate the efficacy and long-term safety of linagliptin added to basal insulins in type 2 diabetes inadequately controlled on basal insulin with or without oral agents.RESEARCH DESIGN AND METHODSA total of 1,261 patients (HbA1c ≥7.0% [53 mmol/mol] to ≤10.0% [86 mmol/mol]) on basal insulin alone or combined with metformin and/or pioglitazone were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo for ≥52 weeks. The basal insulin dose was kept unchanged for 24 weeks but could thereafter be titrated according to fasting plasma glucose levels at the investigators’ discretion. The primary end point was the mean change in HbA1c from baseline to week 24. The safety analysis incorporated data up to a maximum of 110 weeks.RESULTSAt week 24, HbA1c changed from a baseline of 8.3% (67 mmol/mol) by −0.6% (−6.6 mmol/mol) and by 0.1% (1.1 mmol/mol) with linagliptin and placebo, respectively (treatment difference −0.65% [95% CI −0.74 to −0.55] [−7.1 mmol/mol]; P < 0.0001). Despite the option to uptitrate basal insulin, it was adjusted only slightly upward (week 52, linagliptin 2.6 IU/day, placebo 4.2 IU/day; P < 0.003), resulting in no further HbA1c improvements. Frequencies of hypoglycemia (week 24, linagliptin 22.0%, placebo 23.2%; treatment end, linagliptin 31.4%, placebo 32.9%) and adverse events (linagliptin 78.4%, placebo 81.4%) were similar between groups. Mean body weight remained unchanged (week 52, linagliptin −0.30 kg, placebo −0.04 kg).CONCLUSIONSLinagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight.

Clinical use of dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in combination therapy for type 2 diabetes mellitus

“…Findings from a separate study of linagliptin as add-on to basal insulin with or without metformin or pioglitazone showed similar improvements in HbA1c and FPG from baseline at 24 weeks with the addition of linagliptin as a third agent (p < 0.001 vs dual therapy) [37]. Also reported were outcomes from a subgroup analysis in which no interaction with linagliptin was observed in patients stratified by renal function, type of basal insulin, age, use of OADs, sex, and body mass index.…”

“…Also reported were outcomes from a subgroup analysis in which no interaction with linagliptin was observed in patients stratified by renal function, type of basal insulin, age, use of OADs, sex, and body mass index. However, significant treatment interactions (p < 0.10) were observed for baseline HbA1c, geographical region, race, and time since diagnosis [37].…”

Safety and efficacy of sitagliptin in combination with transient continuous subcutaneous insulin infusion (CSII) therapy in patients with newly diagnosed type 2 diabetes

“…Recently, DPP-4 inhibitor became one of second-line regimens after metformin in the treatment of type 2 diabetes in the position statement suggested by the American Diabetes Association and the European Association for the Study of Diabetes [25]. Previous studies have shown that DPP-4 inhibitors can significantly decrease HbA1c concentration when added to insulin regimens, without an additional risk of hypoglycemia [8][9][10][11]. A study indicated that add-on therapy with sitagliptin to various insulin regimens could decrease daily insulin doses and improve glycemic control without severe hypoglycemia and/or weight gain [13].…”

“…Rosenstock et al showed that the addition of alogliptin to the existing insulin therapy significantly improved the glycaemic control of patients with type 2 diabetes, when it was previously controlled inadequately by insulin alone [10]. A 52-week randomized, double-blind study showed linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight [11]. Vilsboll et al showed that the addition of sitagliptin to insulin therapy in a 24-week study improved the glycaemic control of patients with type 2 diabetes.…”

Efficacy and Safety of Linagliptin in Subjects With Long-standing Type 2 Diabetes Mellitus (>10 Years): Evidence From Pooled Data of Randomized, Double-blind, Placebo-controlled, Phase III Trials

“…Overall, 84% of patients in this study reported a disease duration of 45 years; in this subgroup of patients, the placeboadjusted mean change in HbA 1c from baseline at week 24 was -0.72%. 32 Also of note, in a 24-week study of the efficacy and safety of linagliptin in patients with T2DM inadequately controlled by metformin and a sulfonylurea, 73% of patients reported a disease duration of 45 years, and the placebo-adjusted mean change in HbA 1c from baseline at week 24 was -0.62% (95% CI, À0.73 to À0.50%; P o 0.0001). 33 In this study, the incidence of hypoglycemia was more common with linagliptin than with placebo.…”