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

Abstract

Aims: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. Methods:A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5-12.0%, were randomized 1:1 to double-blind, free-combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245). Results:The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by -2.8 ± 0.1% with linagliptin/metformin and -2.0 ± 0.1% with linagliptin; a treatment difference of -0.8% (95% confidence interval -1.1 to -0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean ± s.e. changes in HbA1c of -2.7 ± 0.1% and -1.8 ± 0.1%, respectively; treatment difference of -0.9% (95% CI -1.3 to -0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (-1.3 kg between-group difference; p =0.0033). Conclusions:Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy.

Risk of any hypoglycaemia with newer antihyperglycaemic agents in patients with type 2 diabetes: A systematic review and meta‐analysis

“…Almost all (140/144) studies reported on drop‐out rates between treatment arms. Of these, one third of studies (42/140 or 30%) were considered high risk of attrition bias, either due to a higher drop‐out rates in the treatment compared to placebo arms or specific mention of participant study withdrawal due to hypoglycaemia . Six studies were found to have a high risk of bias for selective reporting, either for providing only a range of hypoglycaemia outcomes or reporting hypoglycaemia data only for the extension phase or insufficient details on the severity of episodes …”

Linagliptin and pioglitazone combination therapy versus monotherapy with linagliptin or pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial

“…2,3 Although this study did not evaluate patients with marked hyperglycaemia, a previous study showed that the initial combination of linagliptin plus metformin achieved large reductions in HbA 1c levels in patients with a mean baseline HbA 1c level of 9.8%, without increasing hypoglycaemia or other adverse effects compared with linagliptin monotherapy. 31 The improvements in efficacy from using an intensive combination treatment strategy should not be at the expense of worsening safety and tolerability profiles. In this study, there were no clinically meaningful differences in the frequencies of AEs between treatment groups.…”

Initiating therapy in patients newly diagnosed with type 2 diabetes: Combination therapy vs a stepwise approach

“…Compared with stepwise therapy, combination therapy offers some potential advantages, including earlier and greater reductions in HbA1c, and may allow greater preservation and restoration of β‐cell function. Clinical trials have demonstrated that, in patients newly diagnosed with T2D, combination treatment using therapies with complementary mechanisms results in faster and greater HbA1c reductions, and more rapid achievement of glycaemic targets, compared with initial monotherapy . A systematic review and meta‐analysis of 15 randomized controlled trials (RCTs) showed that initial therapy with metformin combined with other oral agents (TZDs, insulin secretagogues, DPP‐4 inhibitors, or SGLT2 inhibitors) resulted in significant improvements in HbA1c and increases in attainment of glycaemic goals (HbA1c <7.0%) compared with metformin monotherapy .…”