CME Writer: Vicki Brower
Study Authors: Matthew J. O’Brien, Susan L. Karam, et al.
Target Audience and Goal Statement:
Endocrinologists, cardiologists, internists, and family medicine specialists
The goal was to measure the cardiovascular (CV) outcomes of second-line antidiabetic medication (ADM) classes after first-line use of metformin in patients with type 2 diabetes (T2D).
- What are the CV risks of second-line ADMs (following first-line metformin)?
- Which are the safest second-line ADMs, and which are the most harmful?
Study Synopsis and Perspective:
Cardiovascular (CV) disease is the leading cause of illness and death in T2D, prompting researchers to compare short-term CV outcomes in patients treated with older medications, including sulfonylureas (SFUs, including meglitinides) and basal insulin, with another older class of treatments, thiazolidinediones (TZDs), and with newer classes of drugs, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors.
Reporting new results about CV harm from some ADMs in JAMA Network Open, lead author Matthew O’Brien, MD, of the Northwestern Feinberg School of Medicine in Chicago, and colleagues noted, “After metformin, current guidelines recommend selecting ADMs based on expected glycemic improvements, potential risks, and other factors, such as their effect on body weight. Some experts suggest that clinicians also consider cardiovascular benefits and harms when prescribing second-line ADM therapy. However, limited cardiovascular data are currently available for the large population of patients starting second-line ADMs after metformin alone is not sufficient or not tolerated.” The researchers added: “Our analysis provides preliminary evidence needed by patients, clinicians, insurance plans, and pharmacy benefit managers to weigh the comparative cardiovascular harms and benefits of each second-line ADM class in this understudied population.”
O’Brien and colleagues found that 2 commonly used diabetes drugs — basal insulin and sulfonylureas — were associated with significantly increased cardiovascular risk when given as second-line therapy for patients with T2D. Their retrospective observational cohort study included data on 132,737 insured adult patients with T2D who were enrolled in commercial or Medicare Advantage health insurance plans from 2011 to 2015. Sources of data included patients’ health plan enrollment files, laboratory claims, pharmacy claims, and other insurance claims.
Sulfonylureas were the most common second-line medication taken (47.6% of participants), followed by DPP-4 inhibitors (21.8%), basal insulin (12.2%), GLP-1 receptor agonists (8.6%), TZDs (5.6%), and SGLT-2 inhibitors (4.3%). All participants received a second anti-diabetic medication after metformin and had filled the prescription at least twice.
Compared with DPP-4 inhibitors, which were used as a reference because of their known “neutral effect” on CV outcomes, basal insulin was associated with twice the cardiovascular risk in adults with T2D when used as second-line therapy after metformin (HR 2.03, 95% CI 1.81-2.27). Patients using basal insulin had a 36% increase in risk for cardiovascular events (HR 1.36, 95% CI 1.23-1.49), which included a composite of congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease; 4.4% of patients had CV events. For SFUs, the risk of composite CV events was 36% higher (HR 1.36, 95% CI 1.23-1.49) than the DPP-4 group, with 3.1% taking SFUs experiencing CV events.
Notably, SGLT-2 inhibitors were not linked with any change in cardiovascular risk (HR 0.81, 95% CI 0.57-1.53), nor were TZDs (HR 0.92, 95% CI 0.76-1.11). GLP-1 receptor agonists, however, were associated with a lower incidence of cardiovascular events (HR 0.78, 95% CI 0.63-0.96) and a significant reduction in stroke risk (HR 0.65, 95% CI 0.44-0.97), although these effects were not significant in all sensitivity analyses.
“People should know if the medications they’re taking to treat their diabetes could lead to serious cardiovascular harm,” O’Brien said in a statement. “This calls for a paradigm shift in the treatment of type 2 diabetes.”
Source References: JAMA Network Open online Dec. 21, 2018; DOI:10.1001/jamanetworkopen.2018.6125; and JAMA Network Open 2018 online Dec. 21, 2018; DOI:10.1001/jamanetworkopen.2018.6119
Study Highlights: Explanation of Findings
The study’s authors examined associations between the classes of diabetes medications and cardiovascular outcomes, adjusting for risk factors that included chronic kidney disease, dyslipidemia, hypertension, obesity, and smoking.
During 169,384 person-years of follow up, there were 3,480 incident cardiovascular events in the study. “According to our findings, we only have to prescribe basal insulin to 37 people over 2 years to observe one cardiovascular event, such as a heart attack, stroke, heart failure or amputation,” O’Brien said. “For sulfonylureas, that number was a bit higher — 103 people. But when you apply these numbers to 30 million Americans with diabetes, this has staggering implications for how we may be harming many patients.”
Treatment with GLP-1 receptor agonists was associated with a significant reduction in stroke risk; “no other significant benefits of ADM class were observed for individual cardiovascular outcomes,” authors wrote. In addition, “there was a direction toward cardiovascular benefit among patients starting treatment with SGLT-2 inhibitors compared with DPP-4 inhibitors that did not achieve statistical significance.” Collectively, these findings raise concerns about the cardiovascular safety of sulfonylureas and basal insulin compared with newer ADMs, and suggest that short-term cardiovascular outcomes of newer ADM classes may be similar among patients starting second-line treatment.
Currently, guidelines for second-line treatment recommend selecting ADMs on the basis of expected glycemic improvements, potential risks, and other factors, such as their impact on body weight and cardiovascular benefits and harms, they wrote. Until this analysis, full information was not available on cardiovascular risks of second-line ADMs. Their study provides “preliminary evidence” needed by patients, clinicians, and others to weigh comparative CV risks and benefits of each ADM class, they concluded.
These results will be complemented by an ongoing randomized trial comparing the glucose-lowering effects of all ADMs considered in this study except TZDs and SGLT-2 inhibitors for second-line use.
Authors caution that while they found no statistically significant benefit to SGLT-2 inhibitors, they were only introduced to the market in 2013, thus possibly limiting evidence available due to a lack of statistical power. Use of those drugs and GLP-1 receptor agonists have revealed improvements in mortality, and in some CV events in patients with serious CV disease, they wrote. In spite of other studies which show harm with SFUs, their study indicates that in spite of harms shown from SFUs, they are still widely prescribed. Other studies show common mechanisms linking basal insulin and SFNs with increased CV risk, including hyperinsulinemia, weight gain, and hypoglycemia.
“Clinicians may consider prescribing GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT-2 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin,” O’Brien said. “Furthermore, our findings may suggest a role for these newer ADMs in managing cardiovascular risk among patients with type 2 diabetes who either are taking metformin alone or have received no ADM previously.”
In an accompanying editorial, Alison Callahan, PhD, and Nigam Shah, PhD, both of the Center for Biomedical Informatics Research at Stanford University School of Medicine in California, said the study was well-designed and provided important information to clinicians. “Recommendations vary for second-line treatment of type 2 diabetes, with little consensus even among clinical guidelines in which the primary endpoint is maintenance of a blood hemoglobin A1c level less than 7%,” they stated.
“Multiple prior studies also have contradictory results in terms of risk of adverse outcomes, including cardiovascular events and kidney disease,” Callahan and Shah continued. “The study by O’Brien [and colleagues] makes an important contribution to this area, by assessing the effectiveness of second-line treatment options for type 2 diabetes in reducing the risk of cardiovascular events.”
One potential limitation of the study was the requirement that prescriptions for second-line medications be filled at least twice, authors wrote. “This requirement may have introduced bias if reasons for discontinuation after the first fill were correlated with cardiovascular outcomes. Although this is likely not the case for most ADMs studied here, the systematic exclusion of some patients with early discontinuation of sulfonylureas and basal insulin owing to hypoglycemia may have underestimated the cardiovascular harms reported,” they said.
Robert Eckel, MD, of the University of Colorado in Denver, who was not involved in the study, emphasized other limitations of the study, including its reliance on insurance claims data, which is prone to misclassification; the non-randomized design, prone to selection bias; and the lack of information on patients’ body weight and duration of diabetes, which are important cardiovascular risk factors. It’s also important to remember that basal insulin is often prescribed to patients with poorer glycemic control, who typically have higher HbA1c levels and a longer duration of disease, which affects cardiovascular risk, said Eckel. “Importantly, basal insulin doesn’t cause cardiovascular disease; it’s an association only.”
However, the study does provide some useful data, Eckel told MedPage Today via email: “The sulfonylurea story is strengthened somewhat here — i.e., when compared with DPP-4 inhibitors (so chosen), the cardiovascular disease outcome is less favorable. If these drugs weren’t cheap, their use is questionable at best,” he said.
Jeff Minerd wrote the original story for MedPage Today
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner