Metabolic Syndrome and Pharmacological Interventions in Clinical Development

Abstract

Metabolic syndrome prevalence is between 24 and 27% and poses a significant risk for the development of atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes (T2D), or other comorbidities. Currently, no drugs are approved for metabolic syndrome treatment itself, so the risk factors are treated with therapies approved for cardiac and metabolic conditions. These are approved drugs for dyslipidemia treatment such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, cornerstone antihypertensive drugs, or novel class glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) for T2D and overweight or obesity treatment. We have also evaluated new pharmacological interventions in clinical development that have reached Phase 2 and/or Phase 3 randomized clinical trials (RCTs) for the management of the risk factors of metabolic syndrome. In the pipeline are glucose-dependent insulinotropic polypeptide (GIP), GLP-1, glucagon receptor (GCGR), amylin agonists, and a combination of the latter for T2D and overweight or obesity treatment. Non-entero-pancreatic hormone-based therapies such as ketohexokinase (KHK) inhibitor, growth differentiation factor 15 (GDF15) agonists, monoclonal antibodies (mAbs) as activin type II receptors (ActRII) inhibitors, and a combination of anti-α-myostatin (GFD8) and anti-Activin-A (Act-A) mAbs have also reached Phase 2 or 3 RCTs in the same indications. Rilparencel (Renal Autologous Cell Therapy) is being evaluated in patients with T2D and chronic kidney disease (CKD) in a Phase 3 trial. For dyslipidemia treatment, novel PCSK9 inhibitors (oral and subcutaneous) and cholesteryl ester transfer protein (CETP) inhibitors are in the final stages of clinical development. There is also a surge of a new generation of an antisense oligonucleotide (ASO) and small interfering RNA (siRNA)-targeting lipoprotein(a) [Lp(a)] synthesis pathway that could possibly contribute to a further step forward in the treatment of dyslipidemia. For resistant and uncontrolled hypertension, aldosterone synthase inhibitors and siRNAs targeting angiotensinogen (AGT) messenger RNA (mRNA) are promising new therapeutic options. It would be interesting if a few drugs in clinical development for metabolic syndrome such as 6-bromotryptophan (6-BT), vericiguat, and INV-202 as a peripherally-acting CB1 receptor (CB1r) blocker would succeed in finally gaining the first drug approval for metabolic syndrome itself.