Drugs based on peptides and proteins (PPs) have been widely used in medicine, beginning with insulin therapy in patients with diabetes mellitus over a century ago. Although the oral route of drug administration is the preferred one by the vast majority of patients and improves compliance, medications of this kind due to their specific chemical structure are typically delivered parenterally, which ensures optimal bioavailability. In order to overcome issues connected with oral absorption of PPs such as their instability depending on digestive enzymes and pH changes in the gastrointestinal (GI) system on the one hand, but also their limited permeability across physiological barriers (mucus and epithelium) on the other hand, scientists have been strenuously searching for novel delivery methods enabling peptide and protein drugs (PPDs) to be administered enterally. These include utilization of different nanoparticles, transport channels, substances enhancing permeation, chemical modifications, hydrogels, microneedles, microemulsion, proteolytic enzyme inhibitors, and cell-penetrating peptides, all of which are extensively discussed in this review. Furthermore, this article highlights oral PP therapeutics both previously used in therapy and currently available on the medical market.

Obesity is a chronic disease caused primarily by the imbalance between the amount of calories supplied to the body and energy expenditure. Not only does it deteriorate the quality of life, but most importantly it increases the risk of cardiovascular diseases and the development of type 2 diabetes mellitus, leading to reduced life expectancy. In this review, we would like to present the molecular pathomechanisms underlying obesity, which constitute the target points for the action of anti-obesity medications. These include the central nervous system, brain–gut–microbiome axis, gastrointestinal motility, and energy expenditure. A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become “block-buster” drugs due to their effectiveness in reducing body weight and beneficial effects on the patient’s metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials.

Hypercholesterolemia plays a crucial role in the development of atherosclerosis, but it remains an undertreated and underdiagnosed disease. Taking into consideration the high prevalence of lipid disorders, long duration of the asymptomatic course of the disease, life-threatening complications resulting from inaccurate therapy, and stringent treatment goals concerning LDL cholesterol level in the prevention of cardiovascular events, novel lipid-lowering therapies have been introduced in the last few years. In this article, a drug belonging to the group of small interfering RNA (siRNA) called inclisiran is described. It is a novel molecule that increases the number of LDL receptors (LDLRs) on the surface of hepatic cells by preventing the formation of proprotein convertase subtilisin/kexin type 9 (PCSK9) responsible for the degradation of LDLRs. With great potential for lowering plasma LDL cholesterol level, high liver specificity, comfortable dosing regimen, and good tolerance without significant adverse effects, it could play an important part in future hypolipemic therapies.

Background/Objectives: Hypercholesterolemia, accompanied by vascular inflammation, leads to the premature initiation and progression of atherosclerosis, and both are considered nowadays as well-established cardiovascular (CV) risk factors. For several years, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is), drugs that reduce the degradation of the receptors for low-density lipoprotein cholesterol (LDLRs), have appeared to be a very efficient lipid-lowering therapy among patients with complications resulting from atherosclerotic cardiovascular disease (ASCVD). Previous studies showed that drugs used to fight hypercholesterolemia (predominantly statins) have significant pleiotropic effects, including anti-inflammatory effects. To date, data on the potential impact of PCSK9 inhibitors, especially inclisiran, on the course of inflammation is still lacking. Therefore, we conceived a study to evaluate the effects of inclisiran on the markers of subclinical inflammation (e.g., pentraxin 3 (PTX3), interleukin-18 (IL-18), and soluble cluster of differentiation 40 ligand (CD40L)) and compared their magnitude in patients at high CV risk, with and without established heterozygous familial hypercholesterolemia (HeFH). Methods: A total of 24 patients at high cardiovascular risk, according to European Society of Cardiology (ESC) guidelines, with or without concomitant HeFH diagnosed using Dutch Lipid Clinic Network (DLCN) criteria, were enrolled in this study. Lipid concentrations and levels of subclinical inflammatory markers of atherosclerosis were measured at the beginning and after 3 months of therapy. Results: After three months of therapy with inclisiran, a statistically significant reduction included total cholesterol (TC): study group 1: from 287.6 ± 94.15 to 215.2 ± 89.08 [mg/dL], p = 0.022 and study group 2: from 211.71 ± 52.72 to 147.64 ± 55.44 [mg/dL], p < 0.001, and low-density lipoprotein cholesterol (LDL-c): study group 1: from 180.79 ± 73.33 to 114.65 ± 71.54 [mg/dL], p = 0.031 and study group 2: from 129.62 ± 46.75 to 63.39 ± 43.6 [mg/dL], p < 0.001. Moreover significant drops were observed in concentrations of PTX3: study group 1: from 1336.33 ± 395.15 to 1121.75 ± 351.17 [pg/mL], p = 0.013 and study group 2: from 1610.76 ± 537.78 to 1376.92 ± 529.19 [pg/mL], p = 0.017), and IL-18: study group 1: from 11.89 (9.72–13.98) to 9.15 (8.62–10.06) [pg/mL], p = 0.005 and study group 2: from 11.58 (10.87–16.97) to 9.65 (8.43–10.95) [pg/mL], p = 0.003). There were no significant changes in the levels of sCD40L. Conclusions: This study confirmed the ability of inclisiran to reduce LDL-c levels in patients at high cardiovascular risk just after one dose of the drug. Furthermore, it appeared that beyond its lipid-lowering effect, the drug may also affect some inflammatory processes involved in the initiation and progression of atherosclerosis.

The phenomenon of contrast-induced nephropathy (CIN) and contrast-associated nephropathy (CAN) has been acknowledged for an extensive duration. Recently, there has been a significant rise in research on the topic due to the enhanced availability of imaging investigations. This theory has been thoroughly validated and extensively reported in the scholarly literature. The primary risk factors are chronic kidney disease, diabetes, sepsis, critical illness, circulatory shock, anemia, advanced age, inadequate hydration, and the use of nephrotoxic medications. The principal preventive strategies are the use of iso-osmolar contrast agents and sufficient hydration, which includes the use of intravenous isotonic saline. The administration of N-acetylcysteine has been shown to decrease the occurrence of CIN without impacting outcomes like mortality or the need for dialysis. Recently, a growing number of scholarly studies have contested this phenomenon, or at least, questioned its clinical significance, rendering it primarily a biochemical occurrence. This review aims to evaluate the previously listed studies. Overestimating the possible dangers of post-contrast nephropathy may diminish the sensitivity of imaging tests that may otherwise utilize contrast, so substantially lowering their clinical relevance. This hypothesis is critically significant to science, medicine, and patients, warranting attention despite the necessity for additional research to validate it. The present study demonstrates that the frequency and importance of CIN may be overestimated.

Atherosclerosis as a multifactorial disease remains the first cause of death worldwide. Current oral lipid-lowering drugs (especially statins) reduce low-density lipoprotein cholesterol (LDLC) levels in the blood, but their clinical efficacy seems to be partially attributed to pleiotropic effects on different pathophysiologic factors of atherosclerosis extending beyond lipid-lowering properties such as anti-inflammatory, antithrombotic and antioxidative features. Novel drugs that interfere with proprotein convertase subtilisin/kexin type 9 (PCSK9) axis of LDL-C receptors (LDLRs) degradation, from the group of monoclonal antibodies (e.g., alirocumab, evolocumab) or small interfering RNA (siRNA), e.g., inclisiran, are effective in reducing LDLC as well. However, data depicting their antithrombotic and antiplatelet activity are scarce, whereas prothrombotic properties of PCSK9 are widely described. Thus, we performed a study to assess the effects of inclisiran on subclinical prothrombotic [fibrinogen, coagulation factor VIII (FVIII), plasminogen activator inhibitor-1 (PAI-1)] and platelet activation markers (platelet factor-4 (PF-4), soluble p-selectin (sCD62P)). Ten patients at high cardiovascular risk with concomitant heterozygous familial hypercholesterolemia (HeFH)—study group 1, and fourteen patients at very high cardiovascular risk without concomitant HeFH—study group 2, were recruited for the study. Lipid profile, subclinical prothrombotic and platelet activation markers were assessed at the beginning and after 3 months of therapy with inclisiran. During therapy, statistically significant reductions in both study groups were seen in total cholesterol levels (study group 1: from 287.6 ± 94.2 to 215.2 ± 89.1 (mg/dL), p = 0.022; study group 2: from 211.7 ± 52.7 to 147.6 ± 55.4 (mg/dL), p < 0.001) and LDL-c (study group 1: from 180.8 ± 73.3 to 114.7 ± 71.5 (mg/dL), p = 0.031; study group 2: from 129.6 ± 46.8 to 63.4 ± 43.6 (mg/dL), p < 0.001). Lipid profile changes were associated with significant decrease in the concentration of FVIII in both groups (study group 1: from 33.3 ± 22 to 22 ± 14.5 (ng/mL), p = 0.006; study group 2: from 37 ±16.9 to 29.3 ±16.4 (ng/mL), p = 0.002) and fibrinogen, but only in study group 2 (from 51.4 (33.2–72.7) to 42.6 (31.3–57.2) (µg/mL), p = 0.035). Among platelet activation markers, a significant decrease in PF-4 in study group 2 was noted (from 286 (272–295.5) to 272 (268–281.5) (ng/mL), p = 0.047). However, there were no statistically significant changes in PAI-1 and sCD62P throughout the study. In our study, inclisiran appeared to be an effective lipid-lowering drug in patients at high cardiovascular risk. Moreover, it was shown that beyond lipid-lowering properties, the drug may also partially affect thrombogenesis and platelet activation.