Choice of therapy in patients with type 2 diabetes inadequately controlled with metformin and a sulphonylurea: A systematic review and mixed-treatment comparison meta-analysis

Open Medicine 06/2012; 6(2):e62-74.
Source: PubMed


Metformin and a sulphonylurea are often used in combination for the treatment of type 2 diabetes mellitus. We conducted a systematic review and meta-analysis to evaluate the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled with metformin and sulphonylurea combination therapy.
MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to November 2009. Additional citations were obtained from the grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected the studies, extracted the data and assessed risk of bias. Key outcomes of interest were hemoglobin A1c, body weight, hypoglycemia, patients' satisfaction with treatment, quality of life, long-term diabetes-related complications, withdrawals due to adverse events, serious adverse events and mortality. Mixed-treatment comparison meta-analyses were conducted to calculate mean differences between drug classes for changes in hemoglobin A1c and body weight. When appropriate, pairwise meta-analyses were used to estimate differences for other outcomes.
We identified 33 randomized controlled trials meeting the inclusion criteria. The methodologic quality of the studies was generally poor. Insulins (basal, biphasic, bolus), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues and thiazolidinediones (TZDs) all produced statistically significant reductions in hemoglobin A1c in combination with metformin and a sulphonylurea (-0.89% to -1.17%), whereas meglitinides and alpha-glucosidase inhibitors did not. Biphasic insulin, bolus insulin, and TZDs were associated with weight gain (1.85-5.00 kg), whereas DPP-4 inhibitors and alpha-glucosidase inhibitors were weight-neutral, and GLP-1 analogues were associated with modest weight loss. Treatment regimens containing insulin were associated with increased hypoglycemia relative to comparators, but severe hypoglycemia was rare across all treatments.
Third-line agents for the treatment of type 2 diabetes are similar in terms of glycemic control but differ in their propensity to cause weight gain and hypoglycemia. Longer-term studies with larger sample sizes are required to determine if any of the drug classes are superior with regard to reducing diabetes-related complications.

Download full-text


Available from: Chris Cameron, Mar 30, 2014
  • Source
    • "When such combination therapy can no longer maintain acceptable glycaemic control, many other antihyperglycaemic agents are available to be added as the third agent of triple therapy. McIntosh et al. conducted a systematic review and meta-analysis of 33 controlled trials to evaluate the comparative safety and efficacy of various classes of antihyperglycaemic therapies in this scenario [15]. Insulins, DPP-4 inhibitor, glucagon-like peptide-1 (GLP-1) analogues, and thiazolidinediones (TZDs) all produced statistically significant reductions in HbA1c ranging from −0.89% to −1.17%, whereas meglitinides and alpha-glucosidase inhibitors did not. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims. The aim of this study is to examine the efficacy of adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to patients with type 2 diabetes inadequately controlled by metformin and sulphonylurea combination treatment. The response of Asian and non-Asian patients to this regimen was also examined. Methods. The medical and computerized records of 80 patients were examined. These patients had baseline HbA1c levels ranging from 7.0 to 12.5% and had a DPP-4 inhibitor add-on therapy for a minimum period of 12 weeks. The primary endpoint was the change in HbA1c level before and after DPP-4 inhibitor treatment. Results. During oral triple therapy, there was a reduction of HbA1c from 8.3% (7.7-8.9) to 7.2% (6.8-7.6) and 26 patients (32.5%) achieved an HbA1c <7%. Poor baseline glycaemic control, lower BMI, and younger age were associated with a better response, but duration of diabetes and gender did not affect outcome. The HbA1c reduction was not different between Asians and non-Asians group [-1.00% (0.6-1.3) vs -0.90% (0.4-1.6)]. Conclusions. DPP-4 inhibitor as a third-line add-on therapy can achieve significant glycaemic improvement in patients with type 2 diabetes inadequately controlled on the combination of metformin and sulphonylurea. The improvement in HbA1c was similar between Asian and non-Asian patients.
    Full-text · Article · Aug 2014 · International Journal of Endocrinology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ipragliflozin (ASP1941) is a selective sodium glucose cotransporter 2 inhibitor in clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM). The primary objective was to evaluate the safety profile and tolerability of ipragliflozin as a glucose-lowering agent in combination with stable metformin therapy in patients with T2DM. A secondary objective was to evaluate the effect of ipragliflozin on the pharmacokinetic (PK) properties of metformin. Thirty-six patients with T2DM stable on metformin therapy (850, 1000, or 1500 mg bid) were randomized in a double-blind manner to receive ipragliflozin (300 mg qd; n = 18) or matching placebo (n = 18) for 14 days. Safety profiles, including monitoring of hypoglycemic events, treatment-emergent adverse events (TEAEs), laboratory measurements, and vital signs were assessed throughout the study. The PK properties of metformin and ipragliflozin were determined in plasma. The geometric mean ratio and its 90% CI for the maximum plasma concentration and AUC(0-10) were calculated for metformin + ipragliflozin (day 14) versus metformin alone (day -1). Pharmacodynamic properties were assessed by measurement of urinary glucose excretion over 24 hours (UGE(0-24)). All the TEAEs, except 1, were mild. Fifteen TEAEs were observed in the ipragliflozin group (7 of 18 patients [38.9%]), and 19 TEAEs were observed in the placebo group in (8 of 18 patients [44.4%]). Treatment-related TEAEs were reported by 3 of 18 patients (16.7%) receiving metformin + ipragliflozin and by 5 of 18 patients (27.8%) receiving metformin + placebo. No hypoglycemic events (blood glucose level <54 mg/L [to convert to millimoles per liter, multiply by 0.0555]) were observed. The geometric mean ratios for C(max) and AUC(0-10) of metformin + ipragliflozin versus metformin alone were 1.11 (90% CI, 1.03-1.19) and 1.18 (90% CI, 1.08-1.28), respectively. After ipragliflozin treatment, UGE(0-24) on day 14 (74.9 g) was significantly higher than that in the placebo group (3.6 g) and at baseline (3.3 g). Combination treatment for 14 days with ipragliflozin and metformin was well tolerated in patients withT2DM without hypoglycemia. The addition of ipragliflozin (300 mg qd) to metformin therapy did not result in a clinically relevant change in the PK properties of metformin. identifier: NCT01302145.
    No preview · Article · Jul 2012 · Clinical Therapeutics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The broadly used combination of metformin and sulphonylurea often fails to bring patients to glycaemic goal. This study assessed the efficacy and safety of vildagliptin as add-on therapy to metformin plus glimepiride combination in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control. A multicentre, double-blind, placebo-controlled study randomized patients to receive treatment with vildagliptin 50 mg bid (n = 158) or placebo (n = 160) for 24 weeks. After 24 weeks, the adjusted mean change in haemoglobin A1c (HbA1c) was -1.01% with vildagliptin (baseline 8.75%) and -0.25% with placebo (baseline 8.80%), with a between-treatment difference of -0.76% (p < 0.001). Significantly more patients on vildagliptin achieved the HbA1c target <7% (28.3% vs. 5.6%; p < 0.001). The difference in fasting plasma glucose reduction between vildagliptin and placebo was -1.13 mmol/l (p < 0.001). In subgroup of patients with baseline HbA1c ≤8%, vildagliptin reduced HbA1c by 0.74% from baseline 7.82% (between-treatment difference: -0.97%; p <0.001) with significantly more patients achieving the HbA1c target <7% (38.6% vs. 13.9%; p = 0.014). Vildagliptin was well tolerated with low incidence of hypoglycaemia, slightly higher than with placebo (5.1% vs. 1.9%) and no clinically relevant weight gain. Vildagliptin significantly improved glycaemic control in patients with T2DM inadequately controlled with metformin plus glimepiride combination. The addition of vildagliptin was well tolerated with low risk of hypoglycaemia and weight gain. This makes vildagliptin an attractive treatment option for patients failing on metformin plus sulphonylurea particularly in patients with baseline HbA1c ≤8%.
    Full-text · Article · Nov 2013 · Diabetes Obesity and Metabolism
Show more