Microvascular Protective Effects Vary Among Anti-diabetic Drugs

Beyond their glucose-lowering effects, the pharmacological mechanisms of certain anti-diabetic medications have been shown to positively impact microvascular health. To investigate further, a recent meta-analysis reviewed a series of randomized controlled trials (RCTs) reporting on microvascular complications in patients with type 2 diabetes taking various diabetes drugs. It found that microvascular protective abilities appeared to differ among drug classes; for instance, while conventional medications like metformin and sulfonylureas were found to have limited or no significant protective effect against microvascular complications, newer drugs such as sodium-glucose co-transporter inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) demonstrated potentially meaningful benefits. It’s possible that medications prescribed to patients with type 2 diabetes could have a positive effect on diabetic microvascular complications beyond their anti-hyperglycemic properties. However, due to the ambiguity of results from current studies, more research is needed to evaluate the specific effects of these drugs. Photo: Carolyn Majcher, OD. Click image to enlarge. The systematic review analyzed a total of 54 RCTs obtained from various databases, encompassing a diverse cohort of adult participants diagnosed with type 2 diabetes. Researchers assessed a pool of clinical outcomes—specifically diabetic retinopathy, nephropathy and peripheral neuropathy—to evaluate the efficacy of different non-insulin anti-diabetic medications.The results of the analysis, published earlier this week in BMC Endocrine Disorders, revealed that there is limited evidence to support the effectiveness of traditional anti-diabetic medications like metformin, sulfonylureas, repaglinide and α-glucosidase inhibitors in managing diabetic microvascular complications as standalone treatments. While no significant change in estimated glomerular filtration rate (eGFR) was noted, findings from two trials indicated that thiazolidinediones significantly lowered urinary albumin-to-creatinine ratio. Some clinical studies also reported that this drug class was linked to increased visual field deterioration and improvements in diabetic retinopathy.Conversely, the two newest meds offered for type 2 diabetes management—the SGLT-2i and GLP-1RA drug classes—demonstrated protective effects against eGFR decline, with the former showing a substantial reduction in urinary albumin-to-creatinine ratio. Furthermore, a recent trial suggested that dipeptidyl peptidase IV inhibitors (DPP-IVi), another commonly prescribed anti-diabetes medication, might lower the risk of diabetic peripheral neuropathy, while GLP-1RAs showed no significant impact on that complication or cardiovascular autonomic neuropathy.The effect of GLP-1 agonists on microvascular complications was most heterogeneous across the analyzed studies, which researchers argue “may be due to the selective criteria for a specific population, the quality and the sample size in some included studies.” While GLP-1RAs were shown to improve eGFR compared to placebo, a large trial known as SUSTAIN 6 found that semaglutide (a GLP-1 RA) could potentially increase the risk of diabetic retinopathy, which the authors note “contrasts with previous results and findings related to other GLP-1 medications, such as liraglutide.”The authors concluded their paper by noting that “besides their anti-hyperglycemic properties, some currently reviewed medications may exhibit unique anti-microvascular abilities.” However, they cautioned, “Due to ambiguous and conflicting available results, more emerging or ongoing trials will address this issue and could benefit clinical strategies for personalized treatment practices.”Click here for the journal source. Wen S, Yuan Y, Li Y, et al. The effects of non-insulin anti-diabetic medications on the diabetic microvascular complications: a systematic review and meta-analysis of randomized clinical trials. BMC Endocr Disord. July 16, 2025. [Epub ahead of print].