Comparative efficacy and safety of antidiabetic drug regimens added to stable and inadequate metformin and thiazolidinedione therapy in type 2 diabetes.

AIMS: Determine the efficacy and safety of antidiabetic agents added-on to metformin and a thiazolidinedione (TZD) in patients with inadequately controlled type 2 diabetes (T2D). METHODS: MEDLINE and CENTRAL were searched for randomised controlled trials (RCTs) evaluating the addition of an antidiabetic agent in patients with T2D inadequately controlled on stable, optimised metformin and TZD therapy (≥ 1500 mg metformin and ≥ 50% maximum TZD dose for ≥ 4 weeks). Frequentist network meta-analysis was performed on identified studies. RESULTS: Eleven RCTs evaluating dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin), sulfonylureas (SUs) (glibenclamide, glimepiride), glucagon-like peptide-1 (GLP-1) analogues (exenatide, liraglutide, dulaglutide, taspoglutide) and sodium-glucose cotransporter2 (SGLT2) inhibitors (canagliflozin, empagliflozin) were identified. The mean reduction in HbA1c from baseline was significant for all agents (range, 0.55-1.17%) vs. placebo. SUs were associated with weight gain (range, 3.31-7.29 kg), while weight loss was seen with all GLP-1 analogues (range, 1.53-2.20 kg) and SGLT2 inhibitors (range, 2.08-2.95 kg) vs. placebo. Relative risk of hypoglycaemia was increased with dulaglutide, exenatide and glimepiride vs. placebo (RR range, 2.65-6.17); and trended higher with all other agents except linagliptin. GLP-1 analogues and canagliflozin reduced systolic blood pressure vs. placebo (range, 2.39-5.05 mmHg). No agent with available data increased the risk of urinary or genital tract infection vs. placebo. CONCLUSION: When added to stable, optimised metformin and TZD, all evaluated antidiabetic agents reduced HbA1c; albeit not to the same degree. Moreover, agents differed in their effects on body weight, hypoglycaemia and systolic blood pressure.

Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis.

AIM: To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy. METHODS: We searched MEDLINE, CENTRAL, clinicaltrials.gov and regulatory websites, and conducted a manual search of references in the identified studies. Randomized trials evaluating antihyperglycaemic agents in adults with Type 2 diabetes experiencing poor glycaemic control despite optimized metformin and sulphonylurea therapy (≥ 1500 mg metformin or maximum tolerated dose; ≥ 50% of maximum sulphonylurea dose for ≥ 3 weeks) were included. Data extraction included: study characteristics; change in HbA1c concentration; weight; systolic blood pressure; and relative risk of hypoglycaemia, urinary tract infections; and genital tract infections. A network meta-analysis was performed. RESULTS: A total of 20 trials evaluating 13 antihyperglycaemic agents were included. Compared with placebo/control, all antihyperglycaemic agents reduced HbA1c levels, albeit by differing magnitudes [range 7 mmol/mol (0.6%) for acarbose to 13 mmol/mol (1.20%) for liraglutide]. Sodium glucose cotransporter-2 inhibitors reduced weight (1.43-2.07 kg) whereas thiazolidinediones, glargine and sitagliptin caused weight gain (1.48-3.62 kg) compared with placebo/control. Sodium glucose cotransporter-2 inhibitors, rosiglitazone and liraglutide decreased systolic blood pressure compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41-8.88 mm Hg). Glargine, thiazolidinediones, liraglutide, sitagliptin and canagliflozin increased hypoglycaemia risk compared with placebo/control (relative risk 1.92-7.47), while glargine and rosiglitazone increased hypoglycaemia compared with most antihyperglycaemic agents (relative risk 2.81-7.47). No antihyperglycaemic agent increased the risk of urinary tract infection, but canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. CONCLUSIONS: When added to metformin and a sulphonylurea, antihyperglycaemic agents had varying effects on efficacy and safety endpoints. These conclusions should be considered when clinicians choose between possible adjunctive agents.

Index clinical manifestation of venous thromboembolism predicts early recurrence type and frequency: a meta-analysis of randomized controlled trials.

BACKGROUND: Observational studies suggest index clinical manifestation of venous thromboembolism (VTE) predicts recurrence type. Data regarding the association between index manifestation and recurrence rates are conflicting. OBJECTIVES: To perform a meta-analysis of randomized controlled trials (RCTs) to determine the type and frequency of recurrent VTE (rVTE) in persons after an index deep vein thrombosis (DVT) or pulmonary embolism (PE). PATIENTS/METHODS: We searched bibliographic databases for RCTs of acute (early) treatment of rVTE in persons with an index DVT or PE (±DVT), enrolling ≥ 50 subjects anticoagulated ≥ 3-months and reporting types of rVTE. We pooled (random-effects) the proportion of rVTEs that were DVTs, PEs, and fatal PEs, the proportion of recurrent PEs that were fatal, and absolute rVTE rates. RESULTS: In nine RCTs (N = 13 640; 413 rVTEs) evaluating persons with an index PE; 66% (95% CI, 60-72%) of rVTEs were PE and 27% (95% CI, 22-33%) were fatal PE. Among 25 RCTs (N = 17 340; 692 rVTEs) evaluating persons with an index DVT, 36% (95% CI, 29-44%) experienced a recurrent PE and 10% (95% CI, 7-13%) a fatal PE. Recurrent PEs following an index PE had a higher fatality rate than after an index DVT (41%; 95% CI, 33-48% vs. 25%; 95% CI, 18-33%; P = 0.007). The rVTE rate was higher following an index DVT compared with a PE (2.6%; 95% CI, 1.6-3.8% vs. 4.9%; 95% CI, 4.0-6.0%; P = 0.002). CONCLUSIONS: Our meta-analysis suggests most rVTEs will be the same type as the index event. While index DVTs are associated with a higher rVTE rate than index PEs; recurrent PEs are associated with high fatality.