Two commonly used diabetes drugs — basal insulin and sulfonylureas — were associated with significantly increased cardiovascular risk when given as second-line therapy for patients with type 2 diabetes (T2D), according to a large observational study.
Compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which were used as a reference, basal insulin was associated with twice the cardiovascular risk in adults with T2D when used as second-line therapy after metformin (hazard ratio 2.03, 95% CI 1.81-2.27), reported Matthew O’Brien, MD, of the Northwestern Feinberg School of Medicine in Chicago, and colleagues.
Basal insulin was associated with 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, O’Brien’s group wrote online in JAMA Network Open.
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors were not linked with any change in cardiovascular risk (HR 0.81; 95% CI 0.57-1.53), nor were thiazolidinediones (TZDs) (HR 0.92, 95% CI 0.76-1.11). Glucagon-like peptide-1 (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, the study found.
“After metformin, current guidelines recommend selecting ADMs [anti-diabetic medications] 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,” the study authors said.
“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 said. “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.”
“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.”
Robert Eckel, MD, of the University of Colorado in Denver, pointed out the many limitations of the study discussed by the authors, 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.
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.
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 affect cardiovascular risk, said Eckel, who was not involved in the study. “Importantly, basal insulin doesn’t cause cardiovascular disease; it’s an association only.”
The retrospective cohort study included data on 132,737 insured adult patients with type 2 diabetes enrolled in commercial or Medicare Advantage health insurance plans during 2011-2015. Sources of data included patients’ health plan enrollment files, laboratory claims, pharmacy claims, and other insurance claims.
All participants were prescribed a second anti-diabetic medication after metformin and had filled the prescription at least twice. Sulfonylureas were the most common second-line medication (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%).
During 169,384 person-years of follow up, there were 3,480 incident cardiovascular events. The study 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.
“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.”
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 end point 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 et al. 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.”
Another potential limitation of the study, O’Brien and co-authors said, was the requirement that prescriptions for second-line medications be filled at least twice. “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.
“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 and colleagues continued. “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.”
O’Brien reported a financial relationship with Novo Nordisk, and a co-author reported financial relationships with Eli Lilly, Novo Nordisk, Lexicon Therapeutics, and Glytec.
Callahan and Shah reported having no conflicts of interest.