A systematic review of the efficacy and safety of triple therapy in patients with type 2 diabetes mellitus not achieving target Ale goals despite existing dual therapy (metformin plus a sulfonylurea)
Creators: name: Kautz, Jordan
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2007

description: Background: For adult patients with type 2 diabetes mellitus and an Ale >7.0% despite maximal oral hypoglycemic therapy with metformin and a sulfonylurea, the relative benefits and harms of triple therapy are unknown. In particular, it is unclear whether patients should commence insulin therapy, either alone or in combination with other agents, or whether desired glycemic control can be attained and maintained with other agents (exenatide, alpha-glucosidase inhibitors, and/or thiazolidinediones). Objectives: To assess the efficacy-as measured by the change in AI c from baseline and by the proportion of patients attaining an Ale <7.0%; safety-as measured by the incidence of hypoglycemia and of treatment-related adverse events; treatment externalities-as measured by the effect on selected cardiovascular risk factors; and health outcomes-as measured by the effect on micro- or macro-vascular complications--of triple therapy. Economic considerations and effects on health-related quality of life are also assessed. Methods: Eligible studies were identified by searching MEDLINE (1977-May 2007) with limits on subjects (humans), language (English), and publication (appearing in peer-reviewed literature). Inclusion criteria included, among others, that trials be randomized with both a minimum duration of follow-up (24 weeks) and an enrolled population (n=30); that at least one study arm investigate triple therapy; and that the authors report on key outcomes. Data extraction and assessment of study quality were undertaken by a single reviewer and made available for review. Results: Eleven randomized controlled trials, enrolling 3,306 participants with a median follow-up duration of 24 weeks, were included. Overall, study methodologic quality was good. Trial participants were generally similar with respect to age, body mass index (BMI), duration of diabetes, and baseline Ale making it possible to generalize the results of this review to a likely externally valid population. Ale lowering varied from 0.2%-1.8% and from least effective (alpha-glucosidase inhibitors) to most effective (thiazolidinediones and insulin glargine). Generalizing these averaged results to patients at differing levels of baseline glycemic control is limited. Irrespective of the third agent chosen, less than half of all trial participants attained Ale <7.0%, though this may reflect inclusion of participants with advanced disease. Nevertheless, results suggest reconsideration of glycemic targets as well as the possible inappropriateness of certain treatment recommendations. Third agents were generally safe and were well-tolerated. The incidence of serious adverse events was low (<3%) including severe hypoglycemia (1.5 events per 100 patient-years). Incidence of hypoglycemia appeared related to the sulfonylurea dose, suggesting a treatment recommendation, and to the ambient level of glycemic control, suggesting a shifting balance of benefits and harms with increasingly intensive therapy. The rarity of serious events precluded comparisons among particular agents. Treatment-related side effects, including their likelihood and severity, are discussed by drug class. Few of the trials reported on micro- or macro-vascular endpoints, economic considerations, or effects on health-related quality of life. The paucity of such data in the included literature has implications for future research. A hypothetical outcomes table is generated to facilitate discussion about the diminishing returns of additional treatment. Conclusions. The efficacy and safety of triple therapy in adults with type 2 diabetes mellitus has not been previously scrutinized in a systematic review. These results can supplement the existing body of knowledge and inform clinical practice. Further research is needed with regard to micro- and macro-vascular outcomes as well as a reconsideration of treatment goals in this population in light of such outcomes. This review further illustrates the validity and necessity of similar analyses being performed along the treatment continuum for patients with type 2 diabetes, to improve both patient-provider decision-making and utilization of health care system resources.