This meta-analysis suggests that sulfonyluria can increase the risk of cardiovascular events and death particularly when compared with meformin. Given widespread use of glimepiride, glipizide and glyburide, more definitive studies are needed to confirm and quantify such a risk.
Speculation: Could CV outcomes be higher because metformin is known to lower it? Do new medications improve events because they are compared, to some degree, with sulfunyluria?
Recent randomized trials have compared the newer antidiabetic agents to treatments involving sulfonylureas, drugs associated with increased cardiovascular risks and mortality in some observational studies with conflicting results. We reviewed the methodology of these observational studies by searching MEDLINE from inception to December 2015 for all studies of the association between sulfonylureas and cardiovascular events or mortality.
Each study was appraised with respect to the comparator, the outcome, and study design–related sources of bias. A meta-regression analysis was used to evaluate heterogeneity. A total of 19 studies were identified, of which 6 DID NOT have major design-related biases. Sulfonylureas were associated with an increased risk of cardiovascular events and mortality in five of these studies (relative risks 1.16–1.55).
Overall, the 19 studies resulted in 36 relative risks as some studies assessed multiple outcomes or comparators. Of the 36 analyses, metformin was the comparator in 27 (75%) and death was the outcome in 24 (67%). The relative risk was higher by 13% when the comparator was metformin, by 20% when death was the outcome, and by 7% when the studies had design-related biases.
The lowest predicted relative risk was for studies with no major bias, comparator other than metformin, and cardiovascular outcome (1.06 [95% CI 0.92–1.23]), whereas the highest was for studies with bias, metformin comparator, and mortality outcome (1.53 [95% CI 1.43–1.65]).
In summary, sulfonylureas were associated with an increased risk of cardiovascular events and mortality in the majority of studies with no major design-related biases. Among studies with important biases, the association varied significantly with respect to the comparator, the outcome, and the type of bias.
With the introduction of new antidiabetic drugs, the use of appropriate design and analytical tools will provide their more accurate cardiovascular safety assessment in the real-world setting.
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It is well established that type 2 diabetes is associated with an increased risk of cardiovascular morbidity and mortality. Although much of this association can be attributed to the long-term complications of this disease, there has been growing interest in determining whether certain antidiabetic drugs influence this risk. In particular, over the years, there have been concerns regarding the cardiovascular safety of sulfonylureas, the second most commonly used antidiabetic drugs after metformin. These safety concerns initiated with the University Group Diabetes Program (UGDP) conducted in the 1960s, where tolbutamide (a first-generation sulfonylurea) was associated with an increased risk of all-cause and cardiovascular mortality compared with placebo. Indeed, sulfonylureas have been associated with weight gain, fluid retention, and hypoglycemia, which are all known cardiovascular risk factors. In contrast, meta-analyses of sulfonylurea randomized controlled trials (RCTs) have produced conflicting findings with respect to cardiovascular events and mortality. However, none of these RCTs were designed or powered to detect cardiovascular events and the RCTs used different comparators, including other oral agents or placebo.
In contrast to the RCTs, several observational studies have associated sulfonylureas with an increased risk of cardiovascular events and death. However, these observational studies used varying approaches to study design and data analysis that could have introduced several biases. With the introduction of new antidiabetic drugs, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) analogs, and sodium–glucose cotransporter 2 (SGLT2) inhibitors, drugs that will likely undergo the same scrutiny as sulfonylureas, there is a need to understand how bias can be introduced (and avoided) in observational studies assessing the safety of second- to third-line treatments. Moreover, many RCTs of the newer drugs have included and will include sulfonylureas in the comparator group.
The objective of this methodological review is to detail the most important methodological limitations of observational studies assessing the cardiovascular safety of sulfonylureas and identify the most robust observational studies of the association between sulfonylureas and the risk of cardiovascular events. This review will thus provide guidance for future studies on the use of robust methods to minimize bias in assessing the cardiovascular safety of newer antidiabetic drugs.
Assessing the cardiovascular safety of second- to third-line antidiabetic drugs can be challenging. As discussed above, certain design and analytical decisions can help circumvent some of these challenges and the biases that ensue. First, given the progressive nature of type 2 diabetes, the primary exposure definition should be based on an as-treated approach or modeling exposure as a time-varying variable. An ITT exposure could also be used to complement the aforementioned exposure definitions but will need to be limited to a relatively short follow-up period (e.g., 1 year) to avoid the exposure misclassification issues described above. Second, it is important to compare drugs used at a similar stage of the disease to avoid time-lag bias. For example, comparing a combination of metformin and sulfonylurea (a second- to third-line treatment strategy) to metformin monotherapy (a first-line treatment strategy) will introduce important confounding by indication that may be difficult to adjust for in the statistical models. The alternative would be to compare a combination therapy with another combination used at a similar stage of the disease, or alternatively match the combination users with monotherapy users on diabetes duration. Third, inclusion of patients in a study should not be based on future events occurring during the follow-up period (such as excluding patients eventually exposed to a specific antidiabetic drug); such inclusion criteria could lead to important selection bias. Instead, such patients should be allowed to be included in the cohort, and other mechanisms such as censoring could be used to mitigate this issue (assuming the censoring is noninformative). Finally, rigorous adjustment of potential confounders is necessary; this can be achieved with the use of methods such as propensity scores or marginal structural models.
In addition to the methodological issues described above, it is important to recognize that there are differences in the pharmacodynamic and pharmacokinetic properties of the different sulfonylureas; these may have an impact on their association with cardiovascular outcomes. Indeed, some sulfonylureas are not selective for pancreatic β-cells and thus may increase the risk of cardiovascular outcomes by binding to receptors in other tissues, such as cardiomyocytes and vascular smooth muscle cells. As such, it will be necessary for future studies to assess the effects of sulfonylureas as a class, as well as the effects of each individual sulfonylurea.
Understanding the cardiovascular effects of sulfonylureas is also important because many RCTs of the newer antidiabetic drugs use sulfonylureas as the comparator drug or include them as part of the comparator regimen. Thus, the safety assessment of these newer drugs can inherently possibly conceal an increased cardiovascular risk if the comparator group includes a treatment that increases this risk. Likewise, it is possible that the benefits on cardiovascular and mortality outcomes observed in some of the recent trials may be due, at least in part, to the fact that a higher proportion of patients in the placebo arms initiated sulfonylureas during the follow-up period. Thus, our present meta-regression analysis of the observational studies to data suggests that some caution be used in interpreting the data from such recent trials when sulfonylureas are involved in the comparator.
The cardiovascular safety of some of the newer antidiabetic agents, such as DPP-4 inhibitors, has also recently been the subject of some concern. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 trial, patients randomized to saxagliptin had a higher risk of hospitalization for CHF compared with placebo (HR 1.27 [95% CI 1.07–1.51]). In contrast, this association was not observed in the vast majority of the observational studies conducted to date, with the exception of two studies. Although the absence of an association in most of these studies provides some reassurance with respect to CHF, the assessment of other cardiovascular outcomes will require careful attention to design-related decisions. As the newer antidiabetic drugs are intended to be used as second- to third-line treatments, it will be imperative that they are compared with drugs used at a similar stage of the disease, and using the appropriate exposure definitions. Failure to consider these important design-related decisions will likely introduce bias and, in the process, generate more uncertainty on the safety of these drugs.
In summary, the majority of the studies reporting on the association between sulfonylureas and cardiovascular risk had design-related biases, such as exposure misclassification, time-lag bias, and selection bias. However, the majority of studies with no major designed-related biases reported increased risks of cardiovascular events and mortality with sulfonylureas. Overall, the role of the comparator drug used had an important bearing on the risk estimates. Indeed, the lowest PRR was for studies with none of the major biases described above, where the comparator was not metformin, and where the event definition was based on a cardiovascular outcome. In contrast, the highest PRR was for studies with major biases, where metformin was the comparator, and where the outcome was mortality. This heterogeneity highlights the need to use appropriate methodological approaches to minimize bias when assessing the safety of second- to third-line antidiabetic drugs. This is highly relevant in this era of new antidiabetic drugs (such as DPP-4 inhibitors, GLP-1 analogs, and SGLT2 inhibitors), where there will be a need to assess their cardiovascular safety in the real-world setting.