Current Reviews in Clinical and Experimental Pharmacology - Online First

Small fiber neuropathy (SFN) affects pain and autonomic function, and there is increasing evidence that immune pathways are linked to its pathology. Intravenous immunoglobulin (IVIG) has been proposed as a treatment option for patients with painful SFN but has yielded mixed results. This review evaluates the effectiveness of IVIGs in the treatment of painful SFN.

According to PRISMA guidelines, a thorough literature search was conducted using five major electronic databases (PubMed, Google Scholar, Scopus, EMBASE, and Web of Science) up to August 17, 2023. Data extraction was performed independently by two reviewers, and quality assessments were performed using Joanna Briggs Institute tools. The PRISMA guidelines ensured the transparency of the review.

This systematic review included seven studies to evaluate the effectiveness of IVIG for the treatment of SFN. The review included 458 patients from various studies conducted between 2005 and 2023, covering various neuropathy subtypes such as idiopathic SFN, sarcoidosis-associated SFN, etc. Both double-blind RCTs reported no significant differences between IVIG and placebo in neuropathy severity or pain reduction. Retrospective cohort studies varied in quality and produced mixed results. Of note, some studies showed significant pain reduction with IVIG, while others did not. The effectiveness of IVIG on neuropathy severity and intraepidermal nerve fiber density was similarly variable, with some studies reporting efficacy and others indicate no significant changes. Overall, IVIG showed potential benefits, but the results were inconsistent across studies.

IVIG shows potential efficacy in select SFN subtypes, particularly autoimmune-associated forms (e.g., TS-HDS/FGFR-3 positive), with some retrospective studies reporting pain and functional improvements. However, two high-quality RCTs found no significant benefit over placebo. Marked heterogeneity in study design, IVIG protocols, diagnostic criteria, and outcome measures limits comparability and generalizability. Adverse events, including infusion reactions were common. These findings highlight IVIG’s possible role in immunologically mediated SFN but underscore the need for standardized protocols, biomarker-based patient selection, and large, well-controlled trials to establish definitive efficacy.

Some evidence suggests the potential benefit of IVIG therapy for certain subgroups of patients with SFN. However, the overall effectiveness is still unclear, and further studies are needed.

Type 2 diabetes mellitus (T2DM) contributes to an increased fracture risk and impaired bone health. The impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on bone fracture risk is unclear. We performed a network meta-analysis (NMA) to assess the impact of DPP-4i on fracture risk in patients with T2DM.

A comprehensive systematic literature search was conducted on PubMed/Medline, Cochrane Library, and ClinicalTrials.gov until June 2024 to identify RCTs reporting fracture events with DPP-4i among T2DM patients. A Bayesian NMA has been performed to calculate the odds ratio (OR) and 95% credible intervals (CrI). Surface under the cumulative ranking analysis (SUCRA) was utilized to assess the rank probability of DPP-4i.

A total of 85 RCTs were identified, including 89,965 T2DM patients with 1,083 fracture events. In the direct meta-analysis, DPP-4i did not elevate fracture risk compared to placebo or other oral anti-diabetics (OADs) (OR (95%CI): 1.04 (0.91-1.18); p=0.57 and 1.18 (0.79-1.74); p=0.96, respectively). Alogliptin and sitagliptin indicated a non-significant trend towards reducing fracture risk compared to placebo (OR (95%CI): 0.59 (0.31-1.15); p=0.12) and OADs (OR (95%CI): 0.73 (0.41-1.30); p=0.28), respectively. In the NMA, alogliptin significantly reduced fracture risk compared to linagliptin and SGLT2i (OR (95%CrI): 0.41 (0.16-0.93) and 0.16 (0.017-0.83), respectively). Conversely, linagliptin increased fracture risk compared to sulfonylurea (OR (95%CrI): 2.3 (1.1-5.2). According to SUCRA, alogliptin (84%) ranked as the preferred treatment for reducing fracture risk in T2DM patients.

Overall, DPP-4i was not associated with an increased risk of fractures in patients with T2DM. However, alogliptin demonstrated a reduced risk of fractures when compared to both linagliptin and SGLT2i. Further long-term clinical studies are needed to confirm the present findings.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. It is associated with life-threatening conditions such as cardiovascular disease and hepatocellular carcinoma. This systematic review and meta-analysis aimed to evaluate ezetimibe in patients with NAFLD.

A comprehensive systematic search was conducted in PubMed, Scopus, Web of Science, and Cochrane CENTRAL up to August 8^th, 2024, to identify relevant articles. The most used keywords for searching are “Ezetimibe” and “Nonalcoholic Fatty Liver Disease.” A random-effects model evaluated the standardized mean difference (SMD) and its 95% confidence interval (CI). All analyses were performed using the “meta” package in the R programming language version 4.3.1.

Ten studies included in our study (five non-controlled and six controlled trials, with a total of 516 participants) investigated the effect of ezetimibe on different parameters. Ezetimibe significantly improves AST (SMD: -0.63, 95% CI: [-1.12, -0.14]), ALT (SMD: -0.50, 95% CI: [-0.91, -0.10]), GGT (SMD: -0.30, 95% CI: [-0.49, -0.10]), and LDL (SMD: -0.85, 95% CI: [-1.16, -0.54]), but was unable to improve HDL, TG, and BMI. Ezetimibe was also able to improve steatosis (SMD: -0.30, 95% CI: [-0.49, -0.10]), but inflammation (SMD: 0.06, 95% CI: [-0.57, 0.69]), ballooning (SMD: -0.62, 95% CI: [-1.55, 0.31]), and fibrosis (SMD: 0.03, 95% CI: [-0.25, 0.31]) were not improved.

Based on the findings, the administration of ezetimibe can reduce liver enzymes as well as the hepatic steatosis, but its effects on liver inflammation and fibrosis remain controversial. Further research is required to study its effects in combination with other treatments.

CRD4204609599.

Statin-induced myopathy (SIM) is a prevalent adverse event impacting treatment adherence. Despite extensive exploration of single nucleotide polymorphisms (SNPs), conflicting evidence obscures their role in SIM incidence, prompting this network meta-analysis.

Observational studies meeting eligibility criteria (patients on any statin with reported SNPs and SIM details) were systematically reviewed. Severe SIM was defined as creatine kinase elevations exceeding 10 times the upper limit of normal. Mixed treatment comparison pooled estimates were generated from direct and indirect pooled estimates, represented by odds ratios (OR) with 95% confidence intervals (CI), and validated via bootstrap analysis.

Thirty-four studies (26,152 participants) examining genotypes spanning drug transporters, metabolizing enzymes, reactive oxygen species production, and myopathy-related genes were analyzed. Significant associations were observed with drug transporters (OR: 1.4; 95% CI: 1.04, 1.5). Notably, solute carrier organic anion transporter 1B1 (SLCO1B1) (rs4149056) exhibited a moderate association with SIM (OR: 2.1; 95% CI: 1.7, 2.6), validated by bootstrap analysis (OR: 2.1; 95% CI: 1.7, 2.8). Similar associations were found for severe SIM with SLCO1B1 (rs4149056) (OR: 3.8; 95% CI: 1.4, 10.4) and ATP Binding Cassette Subfamily B Member 1 (ABCB1) (rs2373588) (OR: 2.8; 95% CI: 1.4, 5.4). Intraclass differences in genetic predictor risks were noted among statins.

Our meta-analysis underscores the significant association of SLCO1B1 with SIM, supporting its clinical utility. Further research is warranted to clarify additional genetic predictors. These findings endorse current guidelines advocating for SLCO1B1 genotyping in statin therapy decisions.