Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs

Abstract

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease.

Fig. 1. Pathways leading to increased platelet aggregability in diabetes mellitus.

Increased platelet reactivity in diabetes involves higher levels of thrombin generation, increased production of thromboxane A₂ (TXA₂), hyperresponsiveness of proteinase-activated receptor 4 (PAR4) to thrombin and TXA₂, and increased platelet membrane expression of P-selectin, adhesion molecules, and glycoprotein (GP) IIb/IIIa. Signalling of P2Y purinoceptor 12 (P2Y₁₂ receptor) — the main platelet receptor for ADP — is also increased. Vascular synthesis of nitric oxide (NO) and prostaglandin I₂ (PGI₂; also known as prostacyclin) is decreased, and the production of reactive oxygen species (ROS) is increased. P2X, P2X purinoceptor; P2Y₁, P2Y purinoceptor 1; vWF, von Willebrand factor.

Fig. 2. Intracellular pathways underlying procoagulant patterns in diabetes mellitus.

Fat tissue produces less adiponectin and is infiltrated by macrophages that release tumour necrosis factor (TNF), IL-1, and IL-6. This inflammatory state increases the synthesis of plasminogen activator inhibitor 1 (PAI1) and tissue factor (TF) by endothelial cells, as well as coagulation factors, carboxypeptidase B2 (also known as thrombin-activable fibrinolysis inhibitor; TAFI), PAI1, and acute phase proteins, such as complement C3, by the liver. TNF blocks the vasculoprotective insulin pathway involving insulin receptor substrate (IRS)–phosphoinositide 3-kinase (PI3K)–RACα serine/threonine-protein kinase (AKT) and activates inflammation through the signalling pathway involving c-Jun N-terminal kinase (JNK)–inhibitor of nuclear factor-κB kinase (IKK)–nuclear factor-κB (NF-κB). Impaired IRS–PI3K–AKT transduction alters nitric oxide (NO) and insulin-responsive glucose transporter type 4 (GLUT4; also known as SLC2A4) function, whereas the prothrombotic insulin pathway involving growth factor receptor-bound protein (GRB)–mitogen-activated protein kinase (MAPK) remains effective. Inflammation also blunts peroxisome proliferator-activated receptor-γ (PPARγ)-mediated synthesis of the anticoagulant tissue factor pathway inhibitor (TFPI). Hyperglycaemia increases production of reactive oxygen species (ROS) and contributes to endothelial dysfunction. Increased levels of glycated haemoglobin (HbA_1c) alter the physiological transport and release of NO. Hyperglycaemia and triglyceridaemia favour the synthesis of coagulation factors and PAI1.

Fig. 3. Anticoagulation in patients with diabetes mellitus and atrial fibrillation.

Pooled event rates of the various outcome measures from phase III trials comparing non-vitamin K antagonist oral anticoagulants (blue) versus warfarin (red) for the treatment of patients with diabetes and atrial fibrillation. RR, risk ratio.

Fig. 4. Antithrombotic therapies in patients with diabetes mellitus and venous thromboembolism.

Recommendations on antithrombotic strategies for the prevention and treatment of venous thromboembolism in patients with diabetes are similar to those for the general population. PE, pulmonary embolism.

Fig. 5. Potential pleiotropic actions of SGLT2 inhibitors and incretin-based therapies for the reduction of thrombotic events.

Several conditions contribute to a prothrombotic state in diabetes mellitus, including (but not limited to) hyperglycaemia, hypertension, obesity, insulin resistance, and impaired kidney function. The results of cardiovascular outcome trials and ad hoc studies suggest that both sodium/glucose cotransporter 2 (SGLT2) inhibitors and incretin hormones can counteract these conditions (to different extents and through different pathways), with possible benefits on the diabetic prothrombotic milieu. Some evidence also suggests a direct regulation of platelet activity by glucagon-like peptide 1 (dashed line). Thick lines indicate mainly direct actions; thin lines indicate mainly indirect effects. ROS, reactive oxygen species.