Meldonium (3-(2,2,2-trimethylhydrazinium)propionate; MET-88; quaterine, trade-named as Mildronate) is an antiischemic drug developed at the Latvian Institute of Organic Synthesis. It is a clinically used in the treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis, and diabetes. Mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. L-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities, meldonium induces adaptive changes in the cellular energy homeostasis. Since L-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of l-carnitine related metabolites, such as long-chain acylcarnitines and trimethylamine-N-oxide. Meldonium is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients' mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness, and nausea become less pronounced. CNS effects of Meldonium could be mediated by stimulation of the nitric oxide production in the vascular endothelium by modification of the gamma-butyrobetaine and its esters pools. It is hypothesized that mildronate may increase the formation of the gamma-butyrobetaine esters. Meldonium was on the World Anti-Doping Agency’s (WADA) list of drugs being monitored until September 2015, when it was added to the list of banned substances, effective January 1, 2016.

Acadesine, also known as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, AICA-riboside, and AICAR, is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia (ALL) and may have applications in treating other disorders such as mantle cell lymphoma (MCL). The mechanism by which acadesine selectively kills B-cells is not yet fully elucidated. The action of acadesine does not require the tumour suppressor protein p53 like other treatments. This is important, as p53 is often missing or defective in cancerous B-cells. Studies have shown acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. Antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients. Acadesine has anti-ischemic properties that is currently being studied (Phase 3) for the prevention of adverse cardiovascular outcomes in patients undergoing coronary artery bypass graft (CABG) surgery. Adenosine itself has many beneficial cardioprotective properties that may therefore be harnessed by this new class of drugs. Unlike adenosine, acadesine acts specifically at sites of ischemia and is therefore void of the systemic hemodynamic effects that may complicate adenosine therapy. Animal and in vitro studies have established acadesine as a promising new agent for attenuating ischemic and reperfusion damage to the myocardium. Acadesine also possesses the theoretical (but unproven) benefit of attenuating reperfusion injury after acute myocardial infarction (MI). Further research is needed to define the full potential of this unique agent in various clinical situations involving myocardial ischemia.

Reglitazar is a dual agonist of PPAR alpha/PPAR gamma receptors. The drug was tested in phase II clinical trial, however, its development was terminated.

Vildagliptin, previously identified as LAF237, is a new oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucaon release by the alpha cells of the islets of Langerhans in the pancreas. It is currently in clinical trials in the U.S. and has been shown to reduce hyperglycemia in type 2 diabetes mellitus. While the drug is still not approved for use in the US, it was approved in Feb 2008 by European Medicines Agency for use within the EU and is listed on the Australian PBS with certain restrictions. Vildagliptin is marketed under the trade names Galvus, Zomelis.

Glurenorm is an anti-diabetic drug in the sulfonylurea class. It is used in the treatment of diabetes mellitus type 2. It is an ATP-dependent K+ (KATP) channel blocker. This block causes a depolarization which leads to activation of voltage-dependent Ca channels and Ca2+ influx, and eventually increases insulin release. Minor skin allergies, gastric upsets and other non-specific side effects have been reported. Hypoglycaemic reactions have been reported but they are infrequent. Glurenorm effect increase butadion, chloramphenicol, tetracycline, coumarin derivatives, cyclophosphamide, sulfonamides, MAO inhibitors, thiazide diuretics, beta-blockers, salicylates, alcohol.

Benfluorex under trade name Mediator was launched in 1976 for controlling blood sugar levels in people with type 2 diabetes. In 2009 this drug together with others medicines containing it was withdrawn because of the risk of heart valve disease. The mechanisms by which benfluorex reduces hepatic gluconeogenesis are markedly different from those of metformin, the main antidiabetic compound used in the world. It was suggested that inhibition of gluconeogenesis by benfluorex was, at least in part, due to a decrease in mitochondrial β-oxidation. First, benfluorex decreased acetyl-CoA concentration, which in turn would reduce pyruvate carboxylase activity and release its inhibitory effect on pyruvate dehydrogenase. Second, benfluorex decreased both the ATP-to-ADP and the NAD+-to-NADH ratios, leading to a reduced gluconeogenic flux at the level of 3-phosphoglycerate kinase and GAPDH. Changes in cellular redox state represent probably the main mechanism by which benfluorex reduces glucose production in hepatocytes.

Buformin (1-butylbiguanide) is an oral antidiabetic drug of the biguanide class. AMPK activator. AMPK is a potential therapeutic target in the prevention and the treatment of type 2 diabetes and insulin resistance. Major classes of antidiabetic drugs have been reported to activate AMPK. Buformin exerts its anti-tumorigenic activity via activation of AMPK and inhibition of the mTOR signaling pathways in endometrial cancer cells. Toxicity: guinea pig LD50 subcutaneous 18 mg/kg; mouse LD50 intraperitoneal 140 mg/kg and 300 mg/kg oral. Buformin was withdrawn from the market in many countries due to an elevated risk of causing lactic acidosis.

Troglitazone (TGZ, brand name: Rezulin and Prelay) is a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand, which was developed by Daiichi Sankyo and approved for the US market for the treatment of Type II diabetes mellitus. The drug is used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise, and was not indicated as initial therapy in patients with type 2 diabetes. This drug was withdrawn from the UK market due to liver toxicity. It was removed from the US market in 2000, only 3 years after its introduction and from Japan, shortly afterward. In addition, was conducted a clinical trial for the treatment of patients with advanced liposarcoma by using troglitazone, but the positive result wasn’t obtained. It was shown, that in case of cancer cells troglitazone acted independently of PPAR gamma, by up-regulation of early growth response-1 (Egr-1). Egr-1 transcription factor has been linked to apoptosis and shown to be activated by extracellular signal-regulated kinase (ERK).

Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It is a 39-amino-acid modified peptide with a C20 fatty diacid moiety that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1. Tirzepatide enhances first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. Tirzepatide can also be used off-label for treating obesity. It is currently implemented as a second-line diabetes medication, similar to GLP-1 medications like semaglutide. It is a once-a-week subcutaneous injectable medication with incremental dose increases.

Semaglutide (trade name Ozempic) is a pharmaceutical drug in development by a Danish company Novo Nordisk for the treatment of type 2 diabetes. Semaglutide is a once-daily glucagon-like peptide-1 analog that differs to others by the presence of an acyl group with a steric diacid at Lys26 and a large synthetic spacer and modified by the presence of a α-aminobutyric acid in position 8 which gives stability against the dipeptidylpeptidase-4. Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors. The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase.