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SUMMARY Aim: To compare the long-term safety, tolerability and efficacy of saxagliptin vs. glipizide as add-on therapy to metformin. Methods: Adults with glycated haemoglobin (HbA1c) > 6.5–10% (on stable metformin 1500 mg/day) were randomised to saxagliptin 5 mg/day (n = 428) or glipizide titrated from 5 to 20 mg/day (mean dose 15 mg/day; n = 430) for 52 weeks with a 52-week extension (NCT00575588). Assessment of the long-term safety, tolerability and efficacy of add-on saxagliptin vs. glipizide after 104 weeks was a tertiary objective of the initial 52-week study. Results: Saxagliptin was well tolerated during the 104-week period; 67.1% of patients receiving saxagliptin vs. 72.6% receiving glipizide had 1 adverse event (AE), and few patients (4.9% vs. 5.6%) discontinued owing to AEs. Fewer patients treated with saxagliptin experienced hypoglycaemia (3.5% vs. 38.4% with glipizide; difference, 34.9%, 95% CI, 39.8 to 30.0) or confirmed hypoglycaemia (0 vs. 9.1% with glipizide). Weight loss was observed with saxagliptin (1.5 kg) vs. weight gain with glipizide (+1.3 kg; between-group difference, 2.8 kg, 95% CI, 3.32 kg to 2.20 kg). Change from baseline in HbA1c was 0.41 0.04% with saxagliptin and 0.35 0.04% with glipizide (betweengroup difference, 0.05%, 95% CI, 0.17 to 0.06%). A post hoc analysis showed that the proportion of patients with baseline HbA1c 7% who achieved HbA1c < 7% (observed data) at week 104 was 23.1% for saxagliptin + metformin and 22.7% for glipizide + metformin. Discussion and Conclusion: A lower risk of hypoglycaemia and reduced body weight were observed with saxagliptin vs. glipizide. No other clinically significant differences were observed between groups in safety profile. No significant between-group differences were observed for reductions in glycaemic parameters. After week 24, a smaller weekly rise in HbA1c was observed with saxagliptin vs. glipizide as add-on therapy to metformin. What’s known The achievement of glycaemic control without hypoglycaemia or weight gain is an important goal in the management of patients with T2DM. Because of the progressive nature of T2DM, most patients eventually require combination antihyperglycaemic therapy to achieve and maintain adequate glycaemic control. The efficacy, safety and tolerability of saxagliptin vs. glipizide as add-on therapy to metformin have previously been demonstrated in a 52-week randomised, doubleblind study. What’s new This article describes the results of a 52-week extension of the initial 52-week study comparing saxagliptin vs. glipizide as add-on to metformin. Results were generally consistent with those of the initial study: over 104 weeks of treatment, the addition of saxagliptin to metformin resulted in similar improvements in measures of glycaemic control, with a lower risk of hypoglycaemia and weight gain compared with the addition of glipizide to metformin.

Summary Aim: To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone. Methods and patients: A total of 858 patients [age ≥ 18 years; glycated haemoglobin (HbA1c) > 6.5 – 10.0%; on stable metformin doses ≥ 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA1c achieved with saxagliptin plus metformin was non-inferior to glipizide plus metformin. Results: The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA1c were −0.74% vs. −0.80%, respectively; the between-group difference was 0.06% (95% CI, −0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p

Summary Incretins are gut hormones that elicit insulin secretion after glucose ingestion. The incretin effect describes the enhanced insulin response from orally introduced glucose compared to intravenous glucose. It comprises between 20% and 60% of the postprandial insulin secretion but is diminished in type 2 diabetes (T2D). Glucagon-like peptide-1 (GLP-1) is an important incretin. In vitro and animal experiments demonstrated that GLP-1 increases β-cell mass by stimulating islet cell neogenesis. In vitro data also show the inhibition of apoptosis of islets by GLP-1. The improvement of β-cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1. Furthermore, GLP-1 inhibits glucagon secretion and the risk of hypoglycaemia is extremely rare. It may represent an attractive therapeutic method for T2D due to its multiple effects. However, only 20% of the GLP-1 administered intravenously is estimated to reach circulation biologically intact. Therefore, exenatide and long-acting GLP-1 analogues, both of which are resistant to degradation and classified as incretin mimetics, are under study, as well as a compound that inhibits incretin degradation.

Summary Background and methods Modern antidiabetic therapies should achieve low HbA1c values and avoid hypoglycaemic complications. The registry SIRTA included 1522 patients with type II diabetes mellitus (T2DM) from 306 German medical practices. Patients had an HbA1c > 6.5% under the maximum tolerated metformin dose. If required, they received combination therapy with other antidiabetics according to the guideline of the German Diabetes Society [Deutsche Diabetes Gesellschaft (DDG)] or usual medical practice. Patients were followed up for 6 months. The target criteria included the achievement of HbA1c target values and the emergence of severe hypoglycaemic episodes. Results Most patients (64.0%) were planned to achieve an HbA1c target

Linagliptin treatment for 104 weeks was recently reported to achieve non-inferior glucose-lowering effects compared with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Additional analyses from this randomised, active-controlled, double-blind trial have been performed in individuals completing the study on study drug without requiring rescue therapy. In this population, significantly more patients receiving linagliptin achieved HbA1c7% without hypoglycaemia and without body weight gain after 2 years compared with those receiving glimepiride (54% and 23%, respectively; odds ratio of 3.9, 95% confidence interval 2.6-5.7, p0.0001).

To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone.A total of 858 patients [age ≥ 18 years; glycated haemoglobin (HbA(1c) )6.5 - 10.0%; on stable metformin doses ≥ 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA(1c) achieved with saxagliptin plus metformin was non-inferior to glipizide plus metformin.The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA(1c) were -0.74% vs. -0.80%, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p0.0001) and a divergent impact on body weight (adjusted mean change from baseline -1.1 kg with saxagliptin vs. 1.1 kg with glipizide; p0.0001). There was a significantly smaller rise in HbA(1c) (%/week) from week 24 to 52 with saxagliptin vs. glipizide (0.001% vs. 0.004%; p = 0.04) indicating a sustained glycaemic effect beyond week 24. Excluding hypoglycaemic events, the proportion of patients experiencing adverse events (AEs) was similar (60.0% saxagliptin vs. 56.7% glipizide); treatment-related AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%), attributable to the higher frequency of hypoglycaemia in glipizide patients. Discontinuation rates resulting from AEs were similar (∼4%).Saxagliptin plus metformin was well tolerated, provided a sustained HbA(1c) reduction over 52 weeks, and was non-inferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycaemia.

To investigate the onset of treatment effects over time observed for liraglutide in combination with oral antidiabetic drugs (OADs).This analysis included patients from three phase 3, 26-week, randomised, double-blind, parallel-group trials. Prior to randomisation, patients underwent a run-in and titration period with metformin (Liraglutide Effect and Action in Diabetes-2, LEAD-2), glimepiride (LEAD-1) or metformin plus rosiglitazone (LEAD-4). Patients were then randomised to receive liraglutide (0.6, 1.2 or 1.8 mg once-daily), active comparator and/or placebo. For this analysis, only the 1.2 mg and 1.8 mg liraglutide doses were included. Outcome measures included change in HbA(1c), fasting plasma glucose (FPG), weight and systolic blood pressure (SBP). The safety profile was also investigated.Significant reductions in HbA(1c) were observed within 8 weeks of treatment with liraglutide plus OADs (p0.0001) and maintained until week 26. Furthermore, liraglutide plus OADs led to significant reductions in FPG within 2 weeks (p0.0001) and sustained over 26 weeks. Adding liraglutide to metformin or metformin plus rosiglitazone also led to early reductions and maintained reductions in body weight (within 8 weeks, p0.0001); however, liraglutide treatment plus glimepiride was weight neutral. Rapid reductions in SBP were observed for liraglutide plus OADs (within 2 weeks, p0.05-0.001) and maintained for 26 weeks. Some patients experienced nausea, which for the majority it diminished within 2 weeks.Liraglutide treatment combined with OADs led to rapid improvements in FPG and SBP. Early reductions in HbA(1c) and body weight were also observed. Adding liraglutide to OADs early on may therefore be a good treatment option for patients with type 2 diabetes.