Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study

Aims: To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5-11.0%). Methods: Patients were randomized to receive the initial combination of 30 mg pioglitazone plus 5 mg linagliptin (n = 259) or pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication. Results: After 24 weeks of treatment, the adjusted mean change (+/- s.e.) in HbA1c with the initial combination of linagliptin plus pioglitazone was -1.06% (+/- 0.06), compared with -0.56% (+/- 0.09) for placebo plus pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was -0.51% (95% confidence interval [CI] -0.71, -0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone; -1.8 and -1.0 mmol/l, respectively, equating to a treatment difference of -0.8 mmol/l (95% CI -1.2, -0.4; p < 0.0001). Patients taking linagliptin plus pioglitazone, compared with those receiving placebo plus pioglitazone, were more likely to achieve HbA1c of < 7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of >= 0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). beta-cell function, exemplified by the ratio of relative change in adjusted mean HOMA-IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus pioglitazone patients and none in the placebo plus pioglitazone group. Conclusion: Initial combination therapy with linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment.