To our knowledge, this systematic review is the first to address the comparative effectiveness of newer diabetes medication classes as monotherapy and in combination therapies for a wide range of clinical outcomes in patients with type 2 diabetes. The inclusion of additional trials and drug comparisons since the 2007 review did not provide sufficient evidence to definitively support one drug or combination of drugs over another for long-term clinical outcomes of mortality and macrovascular and microvascular complications of diabetes. When intermediate outcomes were evaluated, most diabetes medications reduced HbA1c levels similarly, by about 1 absolute percentage point (consistent with the 2007 review). Metformin was consistently associated with weight reduction or neutrality compared with most other diabetes medications, which generally increased weight. Overall, medication effects on lipid levels were small to moderate and of uncertain clinical importance. Conclusions on comparative risk for adverse events were clearest for sulfonylureas and meglitinides, which increased the risk for hypoglycemia; for metformin, which was associated with increased gastrointestinal adverse effects; and for thiazolidinediones, which increased risk for heart failure.
Overall, combinations of 2 drugs compared with monotherapy had additive effects, in terms of not only improved glycemic control but also risk for adverse events and weight gain. The comparative benefit of one 2-drug combination over another was not clear. For example, metformin plus a sulfonylurea had efficacy similar to that of metformin plus a thiazolidinedione in reducing HbA1c level and had a lower risk for heart failure, but the risk for hypoglycemia was increased 6-fold.
Although we did not perform a comprehensive review of the addition of insulin to oral medications, we include several clinically relevant comparisons. The addition of premixed insulin to metformin seemed to produce greater reduction in HbA1c level, slightly greater weight gain, and higher risk for hypoglycemia than metformin plus basal insulin.
Two other recent systematic reviews compared add-on treatments with metformin in terms of HbA1c
). One review identified 16 placebo-controlled trials and 11 active-comparator trials of metformin combination therapy and concluded that sulfonylureas plus metformin were superior to thiazolidinediones plus metformin in reducing HbA1c
). In our analyses using direct comparisons, we did not detect a significant difference between these combinations, which was confirmed in a recent network meta-analysis (35
). Our review adds to these recently published reviews by assessing combinations with thiazolidinediones and including more articles and additional meta-analyses.
The American Diabetes Association/European Association for the Study of Diabetes consensus statement has suggested consideration of a GLP-1 receptor agonist as an add-on treatment to metformin if weight gain is a concern (36
), but no explicit recommendations were made regarding DPP-4 inhibitors. The American Association of Clinical Endocrinologists/American College of Endocrinology consensus algorithm recommends use of a DPP-4 inhibitor as one of several options for either initial monotherapy or second-line therapy and a GLP-1 agonist as one of several options for initial combination therapy with metformin when the HbA1c
level is 7.6% or greater (37
). Overall, we found that the DPP-4 inhibitors improved HbA1c
to a lesser extent than metformin as monotherapy, but when added to metformin they reduced HbA1c
levels without additional risk for hypoglycemia. The GLP-1 agonists were associated with weight loss compared with sulfonylureas. We could not draw firm conclusions about most other comparisons for intermediate outcomes, safety, or long-term effects of GLP-1 agonists or DPP-4 inhibitors because few studies were available per drug comparison, but our findings were consistent with those of other recent systematic reviews (38
In September 2010, the FDA placed restrictions on the use of rosiglitazone through a Risk Evaluation and Mitigation Strategy; in part, this will require clinicians to attest to and document that the benefits of the drug outweigh its cardiovascular risks. This decision was made after a federal medical advisory panel concluded that rosiglitazone was associated with myocardial ischemia but voted to keep it on the market (41
). Their conclusion was based on recent observational data (42
) and 2 meta-analyses by Nissen and Wolski (44
), as well as on increased understanding of the pharmacology of rosiglitazone (46
). Other analyses, including the original 2007 review (11
), did not show an elevated risk for myocardial ischemia but had very imprecise point estimates. A notable addition to this update was RECORD, which reported that the combined study groups of rosiglitazone plus metformin and rosiglitazone plus sulfonylurea were noninferior to metformin plus sulfonylurea for the primary end point of hospitalization or death from cardiovascular disease. However, these findings were inconclusive for myocardial infarction, for which a non–statistically significant, slight increase in risk was seen in the 2 combined rosiglitazone (metformin or sulfonylurea plus rosiglitazone) groups (24
). As the FDA acknowledged, RECORD was open-label with a noninferiority design, which may have limited its ability to ascertain the cardiovascular effects of rosiglitazone (49
Our updated review informs the debate about rosiglitazone by providing a comprehensive comparative risk and benefit assessment relative to all other hypoglycemic agents on a wide range of outcomes, not only cardiovascular ischemic risk. We followed a prespecified protocol and engaged a research team that was not invested in either side of the rosiglitazone debate. Overall, other than the risk for heart failure associated with the thiazolidinediones, we found no conclusive evidence of excess ischemic cardiovascular risk associated with rosiglitazone, consistent with the original review. However, the methods for this review differed from those by Nissen and Wolski (44
). We included studies that were done only in people with type 2 diabetes and had active comparators, whereas Nissen and Wolski included studies in people with other chronic diseases as well as placebo-controlled trials (44
). In light of the potential ischemic risk of rosiglitazone and the multiple other available medications to treat diabetes, clinicians will need to determine when the benefits of rosiglitazone outweigh the potential risk for individual patients, in keeping with the FDA’s recommendations.
Our systematic review has limitations. First, because this was an update of a comprehensive review performed 2 years ago, we focused a priori on studies with active-control comparators, which are most relevant for clinical practice. The exclusion of placebo-controlled trials may have implications for the review, including missed rare adverse events. To conclude from an active-control study that one medication is more effective than another requires prior knowledge that the active-control drug has been studied and is known to be more effective than placebo. Because the current review is an update of a review that had included placebo-controlled trials, this was probably true for most drug comparisons (50
). However, this assumption may be less valid for the newer medications saxagliptin, sitagliptin, nateglinide, exenatide, and liraglutide; evidence from other systematic reviews, such as Cochrane reviews, will be helpful in making conclusions about these agents (38
Second, our inclusion criteria required that all studies meet 1 or more of the prespecified comparisons of interest; thus, studies with any number of “background medications” were excluded. Our goal was to avoid contamination with the intervention medications and to clearly identify combinations of medications. This criterion resulted in exclusion of several larger trials (4
), some of which compared HbA1c
-lowering strategies rather than individual medications, and exclusion of some smaller trials and observational studies.
Third, we may have missed some studies and outcomes because our search was limited to English-language articles or because studies selectively reported results. Fourth, limitations of reporting in the included studies limited our ability to combine them in meta-analyses. For example, several studies did not report the significance of reported between-group differences and the measures of dispersion, thereby hindering our efforts to estimate effect size across trials. In addition, some trials underdosed comparison medications, limiting our ability to draw conclusions about efficacy.
Fifth, many included trials were industry-sponsored, raising the possibility of publication bias and other forms of bias, such as selective reporting of outcomes. Although we generally did not find publication bias, the tests had limited power to detect this owing to the small number of studies for many comparisons. Finally, most included studies were small and short with limited ability to detect clinically important harms and benefits most important to patients.
This updated comprehensive systematic review confirms the finding from the 2007 review that metformin, both as monotherapy and in combination with other medications, has the highest benefit–risk profile in most comparisons. Overall, we could not draw firm conclusions about the safety and long-term clinical outcomes of the newest agents, the DPP-4 inhibitors and the GLP-1 agonists, because studies were short-term and had few common comparators. Most 2-drug combinations had similar effects on glycemic control, but some combinations had lower comparative risk for hypoglycemia, weight gain, congestive heart failure, and fractures, which may affect the choice of a second agent. The comprehensiveness of this review allowed us to identify deficiencies in the published literature: most important, the need for future research to evaluate long-term clinical outcomes in higher risk sub-populations, such as different ethnic groups; older adults; and patients with underlying comorbid conditions, who may also have higher event rates.