Insulin, Sulfonylureas Raise Cardiovascular Risk in Diabetes

Miriam E. Tucker

December 21, 2018

Use of insulin or sulfonylureas as second-line treatment in adults with type 2 diabetes is associated with increased cardiovascular risk, whereas use of newer classes of glucose-lowering drugs is not, new real-world research from the United States indicates.

The findings, from a retrospective analysis of national administrative claims data, were published online published online in JAMA Network Open by Matthew J. O'Brien, MD, of the Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, and colleagues. 

Among more than 130,000 insured adults with type 2 diabetes who required a second glucose-lowering agent after metformin, use of insulin or sulfonylureas was associated with consistent cardiovascular harm compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to have a neutral cardiovascular effect.

On the other hand, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones (TZDs) were not associated with cardiovascular harm compared with DPP-4 inhibitors, but they also didn't produce the significant cardiovascular benefit that has been demonstrated in randomized clinical outcome trials of these agents in patients with type 2 diabetes and established cardiovascular disease.

Such high-risk populations have typically been necessary for statistical power in US Food and Drug Administration-mandated cardiovascular outcomes trials (CVOTs), but aren't representative of the adult type 2 diabetes population as a whole, of whom just 18% have established cardiovascular disease. Moreover, CVOTs are conducted on just one drug compared with placebo.   

New Study Targets Area of Significant Clinical Uncertainty

"To date, no studies have directly compared the cardiovascular effects of all contemporary [glucose-lowering drug] options among patients starting second-line therapy...By examining cardiovascular outcomes among patients initiating second-line [glucose-lowering drugs] in the real world, this study aimed to complement findings from individual drug trials and further inform [glucose-lowering drug] choices for the broad population of patients currently receiving these medications," the investigators say.

In an accompanying editorial, Alison Callahan, PhD, and Nigam H. Shah, MBBS, PhD, both of the Center for Biomedical Informatics Research, Stanford University School of Medicine, California, praise the study, noting that it "targets an area of significant clinical uncertainty with the potential to inform the treatment of millions of individuals with type 2 diabetes," and in doing so "makes an important contribution to this area."

Callahan and Shah note that the findings agree with their recent study examining the real-world impact of various classes of second-line glucose-lowering agents on glycemic control and complication rates, including myocardial infarction. This new study makes "a valuable contribution" by adding GLP-1 receptor agonists.

Both studies, they note, "leverage observational data that capture details of healthcare processes and patient outcomes for millions of lives, with significant longitudinal coverage."

Basal Insulin, Sulfonylureas Robustly Associated With CV Harm

The current study included 132,737 adults with type 2 diabetes enrolled in commercial or Medicare Advantage health insurance plans during 2011-2015. All had initiated a second-line glucose-lowering drug, mostly along with metformin. The data were analyzed from January 2017 to October 2018.

Overall, 5.5% had a history of cardiovascular events before starting treatment with the index second-line agent.

Of the prescription fills for those agents, 47.6% were sulfonylureas, 21.8% DPP-4 inhibitors, 12.2% basal insulin, 8.6% GLP-1 agonists, 5.6% TZDs, and 4.3% SGLT2 inhibitors.

The investigators established the DPP-4 inhibitor users as the comparison group because data have shown that class to have a neutral effect on cardiovascular outcomes.

The primary outcome was time to first cardiovascular event after starting the second-line agent, with events defined as hospitalization for congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease. There were 3480 such events during 169,384 person-years of follow-up.

Relative to starting treatment with a DPP-4 inhibitor, and following adjustment for patient, prescriber, and health plan characteristics, the risk for composite cardiovascular events was 36% higher in the sulfonylurea group (HR, 1.36) and more than double with basal insulin (HR, 2.03).

This corresponds to numbers needed to harm during 2 years of treatment with sulfonylureas and basal insulin of 103 and 37, respectively.

Increased relative cardiovascular risk associated with use of sulfonylureas or basal insulin was observed across all individual cardiovascular outcomes and remained "robust" in sensitivity analyses, O'Brien and colleagues report.

Of concern, they point out, "Despite the observed cardiovascular harms associated with initiating sulfonylureas and basal insulin, prescriptions for these two [drug] classes were filled by 60% of patients in our nationwide analysis."

Newer Agents Don't Show Harm or Benefit in Real-World T2D Population

Among the newer agents, use of a GLP-1 agonist was associated with a significantly lower adjusted risk of composite cardiovascular events compared with DPP-4 inhibitor use (hazard ratio, 0.78; 95% CI, 0.63 - 0.96). However, that benefit lost significance in several sensitivity analyses.  

The CV event rates after starting treatment with either SGLT2 inhibitors or TZDs weren't significantly different from those of DPP-4 inhibitors (HR, 0.81 and HR, 0.92, respectively).

O'Brien and colleagues say their work will be complemented by the ongoing randomized Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study, which is comparing long-term glycemic efficacy of a sulfonylurea (glimepiride), a DPP-4 inhibitor (sitagliptin), a GLP-1 agonist (liraglutide), and basal insulin (glargine) added to metformin. Unfortunately, GRADE doesn't include any SGLT2 inhibitors.

In conclusion, the researchers say their new findings "raise concerns about the cardiovascular safety of sulfonylureas and basal insulin," compared with newer glucose-lowering drugs and suggest that short-term cardiovascular outcomes of newer glucose-lowering drug classes may be similar among patients starting second-line treatment.

"Therefore, clinicians may consider prescribing GLP-1 agonists, DPP-4 inhibitors, or SGLT2 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin."

The study was supported through a grant to Northwestern University from UnitedHealthcare Services. O'Brien has reported receiving personal fees from Novo Nordisk outside the submitted work.

JAMA Network Open. Published online December 21, 2018. Abstract, Editorial

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