Biological and Biosimilar Medicines in Contemporary Pharmacotherapy for Metabolic Syndrome

Abstract

The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly being supplemented by biological and biosimilar agents. This trend is particularly evident in the development and advancement of anti-diabetic and hypolipemic therapies. This review explores advances in the treatment of hypercholesterolemia and hypertriglyceridemia, elevated lipoprotein(a) [Lp(a)], diabetes, and obesity associated with metabolic syndrome. It focuses mainly on biopharmaceuticals such as proteins and nucleotide-based drugs (antisense oligonucleotides, small interfering RNA), but also on dipeptidyl peptidase-4 (DPP-4) inhibitors classified as incretin drugs along with glucagon-like peptide-1 (GLP-1) analogues. Due to the substantial role of SGLT-2 (sodium/glucose cotransporter 2) inhibitors in novel diabetes therapies, especially for managing cardiovascular risk, this group of compounds was also included in this review. Many clinical data in the field of effectiveness of biopharmaceuticals in metabolic disorders are provided. Therefore, in this review, we mainly include a brief history of drug development and approval, first synthesis and structure modifications, which relevantly influence pharmacokinetics, and safety. We provide only brief comparison of biological drugs with metformin and sulphonylureas derivatives. Databases such as PubMed, Scopus, and Google Scholar are searched for the period between 2000 and 2024.

Keywords: GLP-1 analogues; biopharmaceutics; discovery; pharmacodynamics; pharmacokinetics; synthesis.

Figure 1

The structures of selected biological drugs used in the treatment of T2D: (a) crystal structure of human zinc insulin at pH 5.5, (b) Trp-cage fortified Tc5b-exenatide chimera (Ex-4-Tc5bQR) at 277K, (c) liraglutide, and (d) semaglutide-bound glucagon-like peptide-1 receptor in complex with Gs protein. The structures and their descriptions are available in the Protein Data Bank [17].

Figure 2

The mechanism of action and pharmacological effects of anti−diabetic drugs. PI3K, phosphatidylinositol 3 kinase; Akt, protein kinase B; GLUT−4, glucose transporter−4; GLP−1, glucagon-like peptide−1; DPP−4, dipeptidyl peptidase−4; GIP, glucose−dependent insulinotropic polypeptide; SGLT−2, sodium−glucose transporter−2.

Figure 3

The structures of DPP-4 inhibitors used in T2D therapy: (a) alogliptin, (b) linagliptin, (c) saxagliptin, (d) sitagliptin, (e) vildagliptin. The structures were prepared with Reaxys.

Figure 4

The structures of phlorizin (a) as a precursor of SGLT-2 inhibitors: (b) dapagliflozin, (c) canagliflozin, (d) empagliflozin. The structures were prepared with Reaxys.

Figure 5

Structure of inclisiran based on Reaxys.