Revisiting ‘intensive’ blood glucose control: A causal directed acyclic graph‐guided systematic review of randomized controlled trials

• Published in: Diabetes, obesity & metabolism Vol. 24; no. 12; pp. 2341 - 2352
• Main Authors: Huang, Chi‐Jung, Wang, Wei‐Ting, Sung, Shih‐Hsien, Chen, Chen‐Huan, Lip, Gregory Y. H., Cheng, Hao‐Min, Chiang, Chern‐En
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2022; Wiley Subscription Services, Inc
• Subjects: antidiabetic agents; Antidiabetics; Blood Glucose; cardiovascular events; Clinical trials; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; dipeptidyl peptidase‐4 inhibitor; Dipeptidyl-Peptidase IV Inhibitors - adverse effects; GLP-1 receptor agonists; Glucagon; glucagon‐like peptide‐1 receptor agonist; Glucose transporter; Glycated Hemoglobin; HbA1c; Humans; Hypoglycemia; Hypoglycemic Agents - adverse effects; Meta-analysis; Microvasculature; Patients; Peptidase; pioglitazone; Randomized Controlled Trials as Topic; Risk assessment; risk factors; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; sodium‐glucose co‐transporter‐2 inhibitor; Systematic review; Thiazolidinediones; type 2 diabetes; cardiovascular events; pioglitazone; risk factors; antidiabetic agents; type 2 diabetes; glucagon-like peptide-1 receptor agonist; sodium-glucose co-transporter-2 inhibitor; meta-analysis; dipeptidyl peptidase-4 inhibitor; HbA1c
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/dom.14819

Aim To clarify the importance of HbA1c reduction and antidiabetic drug use in preventing major adverse cardiovascular events (MACE) for patients with type 2 diabetes (T2D). Materials and Methods We conducted an updated systematic review of contemporary large randomized controlled trials assessing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk in adult T2D patients. Mixed‐effects meta‐regression was performed to examine the associations of HbA1c reduction with subsequent risk of macrovascular and microvascular events. We evaluated the potential mediating role of HbA1c reduction in the relationship between antidiabetic drugs and MACE. Results Eighteen placebo‐controlled trials comprising 155 610 participants were included. The effects of treatment differed among antidiabetic drug classes for most adverse outcomes with high heterogeneity (I2: 63.7%‐95.8%). Mean HbA1c reduction was lowest with dipeptidyl peptidase‐4 inhibitors (0.30%), followed by sodium‐glucose co‐transporter‐2 inhibitors (0.46%), and was highest with glucagon‐like peptide‐1 receptor agonists (0.58%) and thiazolidinediones (0.60%). Lower relative risks of MACE were significantly associated with larger reductions in achieved HbA1c (β −0.3182; 95% CI: −0.5366 to −0.0998; P = .0043), even after adjusting for drug classes. When considering HbA1c lowering as a mediator to be controlled, beneficial effects owing to specific antidiabetic treatment for MACE were not observed (χ2 = 1.4494; P = .6940). The proportion mediated by HbA1c reduction was 50.0%‐63.5% for these antidiabetic agents. Conclusions The main benefits of antidiabetic agents might result from the reduction in blood sugar levels and are generally independent of drugs used. Risk reduction in MACE was proportional to the magnitude of HbA1c decrease conferred by antidiabetic agents with less hypoglycaemic hazard.