Sandra Thiemann

Effects of Adding Linagliptin to Basal Insulin Regimen for Inadequately Controlled Type 2 Diabetes A ≥52-week randomized, double-blind study

OBJECTIVE To 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 METHODS A 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. RESULTS At 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). CONCLUSIONS Linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight.

Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: an 18-week randomized, double-blind, placebo-controlled phase III trial with a 34-week active-controlled extension

To investigate the efficacy and safety of linagliptin, a dipeptidyl peptidase‐4 inhibitor, in type 2 diabetes mellitus (T2DM) patients for whom metformin was inappropriate.

Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: The randomized MARLINA-T2D trial

The MARLINA‐T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard‐of‐care in individuals with type 2 diabetes and albuminuria.

Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes

In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), linagliptin 5 and 10 mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26 weeks compared with placebo and voglibose, respectively. This extension study assessed long‐term tolerability of linagliptin over 52 weeks.

Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial.

To evaluate glucose‐lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted.

Efficacy and safety of linagliptin as add-on therapy to basal insulin and metformin in people with Type 2 diabetes

To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin.

Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: Analysis of pooled events from 19 clinical trials

AIMS To examine the safety and efficacy of linagliptin in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) using pooled data from the global clinical trials program. METHODS Patient-level data were pooled from randomized, placebo-controlled clinical trials of linagliptin (5mg, monotherapy or combination therapy). Safety/efficacy analyses were conducted for patients with CAD and ≥12 and ≥24weeks of treatment, respectively. RESULTS The safety analysis included 19 trials (linagliptin, n=451; placebo, n=272) and the efficacy analysis, 12 trials (linagliptin, n=328; placebo, n=198); mean (± standard deviation) exposure to study treatment was 212 (144) days linagliptin and 245 (171) days placebo. Occurrence of cardiac adverse events (AEs) was similar for linagliptin- and placebo-treated patients (9.1% and 9.2%, respectively); exposure-adjusted incidence rates (per 100 patient-years) were 16.6 and 14.0, respectively. Overall incidence of AEs was numerically lower with linagliptin than placebo. After 24weeks, mean adjusted change (standard error) from baseline glycosylated hemoglobin was -0.64% (0.04) with linagliptin vs. -0.08% (0.05) with placebo (P<.001). CONCLUSIONS This comprehensive pooled analysis showed that addition of linagliptin to treatment regimens of patients with T2DM and CAD was not associated with an increased incidence of cardiac AEs, was well tolerated, and was effective.

Kardiovaskuläre Studien-Endpunkte bei Typ-2-Diabetes und die Sulfonylharnstoff-Kontroverse

Sulphonylureas (SUs) are antidiabetic agents widely used in patients with Type 2 Diabetes Mellitus (T2DM). Observational retrospective studies have raised concerns regarding the cardiovascular (CV) safety of this class of drugs, and data from observational and registry studies are conflicting. To address the SU controversy, this review looked at longer-term RCTs, where SUs were compared in a head-to-head fashion with active comparators. An analysis of 18 studies did not find any increase in the incidence of CV events with SU therapy. However, the available data are limited and most importantly, there is a lack of prospective, adequately powered, formal head-to-head CV outcome trials. Since SUs are still being used as second-line therapy in combination with metformin and in some cases as first-line treatment of T2DM, there is a definite need for CV safety data from a prospective RCT. The CAROLINA(®) study is currently the largest CV outcome study with a direct comparison of an SU and a dipeptidyl peptidase-4 inhibitor (DPP-4). Based on the study design and statistical power of CAROLINA(®), its results will provide a unique perspective regarding CV outcomes of these 2 commonly used agents.

A RANDOMIZED, ACTIVE- AND PLACEBO-CONTROLLED, THREE-PERIOD CROSSOVER TRIAL TO INVESTIGATE SHORT-TERM EFFECTS OF THE DIPEPTIDYL PEPTIDASE-4 INHIBITOR LINAGLIPTIN ON ENDOTHELIAL FUNCTION IN TYPE 2 DIABETES

Studies of dipeptidyl peptidase-4 inhibitors (DPP-4i) report heterogeneous effects on endothelial function in patients with type 2 diabetes. This study assessed the effects of the DPP-4i linagliptin (LINA) vs the sulfonylurea glimepiride (GLIM) and placebo (PBO) on measures of macro- and