Effects of Thiazolidinedione and New Antidiabetic Agents on Stroke

Abstract

Patients with hyperglycemia are at a high risk of cardio-and cerebrovascular diseases. Diabetes patients also have poor outcomes after cerebrovascular disease development. Several classes of drugs are used for diabetes management in clinical practice. Thiazolidinedione (TZD) was introduced in the late 1990s, and new antidiabetic agents have been introduced since 2000. After issues with rosiglitazone in 2007, the U.S. Food and Drug Administration strongly recommended that trials investigating cardiovascular risk associated with new antidiabetic medications should be conducted before drug approval in the United States, to prove the safety of these new drugs and to determine their superiority to previous medications. Currently, results are available from two studies with TZD focusing on cardiovascular diseases, including stroke, and from 12 cardiovascular outcome trials focusing on major adverse cardiovascular events associated with new antidiabetic agents (four with dipeptidyl peptidase-4 inhibitors, three with sodium-glucose cotransporter-2 inhibitors, and five with glucagon-like peptide-1 analogues). These studies showed different results for primary cardiovascular outcomes and stroke prevention. It is important to determine whether prescription of TZD or new antidiabetic medications compared to conventional treatment, such as sulfonylurea or insulin, is better for stroke management. Furthermore, it is unclear whether drugs in the same class show greater safety and efficacy than other drugs for stroke management.

Role of diabetes in stroke: Recent advances in pathophysiology and clinical management

“…A Cochrane review comparing TZDs and placebo for the secondary prevention of stroke and related vascular events in people with a history of stroke or TIA revealed TZD presumably reduced recurrent stroke, improved insulin sensitivity, and reduced recurrent stroke and total events of cardiovascular mortality, non‐fatal myocardial infarction or non‐fatal stroke 133 . This shows that in T2DM and IR patients, TZDs may mitigate the risk of recurrent stroke and related vascular events 130 …”

“…However, the effects of these drugs in improving clinical outcomes in T2DM patients at high risk of stroke or after stroke warrant further studies. The effects of the latest anti‐diabetic drugs or their combination in comparison to conventional treatment on improving cardiovascular outcomes and stroke prevention are inconsistent for use in stroke management; further safety and efficacy studies comparing drugs from different classes are required 130 . Multifactorial interventions involving anti‐diabetic medications especially the new agents such as GLP‐1 RAs, DPP‐4 inhibitors and SGLT2 inhibitors along with lifestyle changes may be a useful preventive strategy in reducing the risk of cardiovascular events including stroke.…”

“…133 This shows that in T2DM and IR patients, TZDs may mitigate the risk of recurrent stroke and related vascular events. 130 with no change in the rate of ischaemic events. However, saxagliptin was associated with an increased rate of heart failure hospitalisation.…”

“…The effects of the latest anti-diabetic drugs or their combination in comparison to conventional treatment on improving cardiovascular outcomes and stroke prevention are inconsistent for use in stroke management; further safety and efficacy studies comparing drugs from different classes are required. 130 Multifactorial interventions involving anti-diabetic medications especially the new agents such as GLP-1 RAs, DPP-4 inhibitors and SGLT2 inhibitors along with lifestyle changes may be a useful preventive strategy in reducing the risk of cardiovascular events including stroke. Furthermore, antiplatelet, or antithrombotic, agents are also useful in primary and secondary prevention of CVD in diabetes.…”

“…130 Whilst certain drugs such as TZD, SGLT2 inhibitors, and several GLP1 analogues have proven to have beneficial cardiovascular outcome profile, the effects of DPP4 inhibitors are neutral when compared to sulfonylurea and insulin. 130 A list of randomised controlled trials (RCTs) on stroke prevention using glucose-lowering therapies in diabetes is provided in Table 1.…”