This systematic review and meta-analysis aimed to determine the association between the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and dementia onset as well as cognitive function in patients with diabetes mellitus. We comprehensively searched the MEDLINE, Embase, and CENTRAL databases to select relevant studies published up to August 2023. The use of SGLT-2 inhibitors significantly lowers dementia risk compared to SGLT-2i non-users (Hazard ratio: 0.68, 95 % CI: 0.50-0.92). Furthermore, our findings indicated a positive effect of SGLT-2 inhibitor use on cognitive function score improvement, as demonstrated by the standardized mean difference of 0.88 (95 % CI: 0.32-1.44), particularly among populations with mild cognitive impairment or dementia. This systematic review and meta-analysis indicate a potential role of SGLT-2 inhibitors in reducing the risk of dementia in patients with diabetes mellitus. These findings underscore the need for well-controlled large clinical trials and future research in this field.

Background: Renin-angiotensin system (RAS) inhibitors have been suggested as protective agents in Parkinson’s disease (PD). However, epidemiological evidence on the association between RAS inhibitors and the development of PD is inconsistent.Objectives: To investigate the effect of RAS inhibitors on PD risk in patients with ischemic heart disease (IHD) by type and cumulative duration of RAS inhibitors and their degree of blood-brain barrier (BBB) penetration ability.Methods: This was a propensity score-matched retrospective cohort study using 2008–2019 healthcare claims data from the Korean Health Insurance Review and Assessment database. The association between RAS inhibitor use and PD in patients with IHD was evaluated using multivariate Cox proportional hazard regression analysis. The risks are presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).Results: Over a 10-year follow-up, 1,086 of 62,228 IHD patients developed PD. The Cox regression model showed that the use of RAS inhibitors was significantly associated with a lower risk of PD (aHR = 0.75; 95% CI 0.66–0.85) than the non-use of RAS inhibitors. Specifically, this reduced risk of PD only remained with the use of BBB-crossing angiotensin II receptor blockers (ARBs) (aHR = 0.62; 95% CI = 0.53–0.74), and this association was more definite with an increasing cumulative duration. A significantly reduced risk of PD was not observed with the use of BBB-crossing angiotensin-converting enzyme inhibitors.Conclusions: The use of ARBs with BBB-penetrating properties and a high cumulative duration significantly reduces the risk of PD in IHD patients. This protective effect could provide insight into disease-modifying drug candidates for PD.

Background: The use of opioid–gabapentinoid combinations has increased, raising several safety concerns. However, meta-analysis studies focusing on this issue are limited.Objective: To evaluate the risk of central nervous system (CNS) depression, gastrointestinal (GI) adverse events, and mortality of combination therapy compared with those of opioid therapy and to explore the differences in the results according to study design and indications.Methods: Relevant studies were selected (published before 30 January 2022) by searching the MEDLINE, Embase, and CENTRAL databases. The pooled odds ratios (OR) with 95% confidence intervals (CI) of the outcomes were estimated using the Mantel–Haenszel method. Subgroup and meta-regression analyses were performed according to study characteristics. Quality assessment was conducted using the Risk of Bias 2 tool for randomized controlled trials (RCTs) and Cochrane Collaboration’s Risk of Bias in non-RCTs tool for non-randomized trials.Results: Adverse events were reported in 26 RCTs and 7 non-RCTs, and mortality was reported in 10 non-RCTs. Compared to opioid therapy, dizziness, cognitive dysfunction, and respiratory depression in combination therapy significantly increased in non-RCTs (OR 3.26, 95% CI 1.82–5.85; OR 3.13, 95% CI 1.51–6.50; OR 1.71, 95% CI 1.31–2.24, respectively), and a similar trend for dizziness and cognitive dysfunction was also identified in the RCT analysis, although the difference was not significant. Combination therapy for cancer pain was associated with the highest risk of sedation in subgroup analysis. Combination therapy significantly decreased the risk of GI adverse events, including nausea, vomiting, and constipation. The mortality risk associated with combination therapy was higher than that associated with opioid therapy (OR 2.76, 95% CI 1.26–6.05).Conclusion: Opioid-gabapentinoid combination therapy could be associated with an increased risk of CNS depression and mortality, despite tolerable GI adverse events. These data suggest that combination therapy requires close monitoring of CNS depression, especially in cancer patients. Caution is needed in interpreting the clinical meanings owing to the lack of risk difference in respiratory depression in the RCT-only analysis and the absence of RCT or prospective studies investigating mortality.

Background: Recent studies on renin-angiotensin system (RAS) inhibitors have reported a reduced risk of Alzheimer’s disease (AD). Nevertheless, the effect of RAS inhibitor type and blood–brain barrier (BBB) permeability on the risk of AD is still unknown.Objectives: To assess the effects of RAS inhibitors on the risk of AD based on the type and BBB permeability and investigate the cumulative duration-response relationship.Methods: This was a population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database records from 2008 to 2019. The data of patients diagnosed with ischemic heart disease between January 2009 and June 2009 were identified for inclusion in the analyses. Propensity score matching was used to balance RAS inhibitor users with non-users. The association between the use of RAS inhibitors and incident AD was evaluated using a multivariate Cox proportional hazard regression model. The results are presented in adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).Results: Among the 57,420 matched individuals, 7,303 developed AD within the follow-up period. While the use of angiotensin-converting enzyme inhibitors (ACEIs) was not significantly associated with AD risk, the use of angiotensin II receptor blockers (ARBs) showed a significant association with reduced risk of incident AD (aHR = 0.94; 95% CI = 0.90–0.99). Furthermore, the use of BBB-crossing ARBs was associated with a lower risk of AD (aHR = 0.83; 95% CI = 0.78–0.88) with a cumulative duration-response relationship. A higher cumulative dose or duration of BBB-crossing ARBs was associated with a gradual decrease in AD risk (P for trend < 0.001). No significant association between the use of ACEIs and the risk of AD was observed regardless of BBB permeability.Conclusion: Long-term use of BBB-crossing ARBs significantly reduced the risk of AD development. The finding may provide valuable insight into disease-modifying drug options for preventing AD in patients with cardiovascular diseases.

Cephalosporins that contain the N-methylthiotetrazole side chain (NMTT-cephalosporin) have been reported to be associated with coagulation-related adverse events; however, a comprehensive evaluation regarding the association is lacking. A systematic review and meta-analysis were conducted to assess the safety profile of NMTT-cephalosporins with respect to hypoprothrombinemia and bleeding. The MEDLINE, Embase, Cochrane, and RISS databases were systematically searched for clinical studies up to October 2018. The association between NMTT-cephalosporins and hypoprothrombinemia was estimated using an odds ratio (OR) with a 95% confidence interval (CI). A total of 15 studies on cefamandole, cefoperazone, cefotetan, cefmetazole, and moxalactam were identified and included in the meta-analysis. Hypoprothrombinemia (OR 1.676, 95% CI 1.275–2.203) and prothrombin time (PT) prolongation (OR 2.050, 95% CI 1.398–3.005) were significantly associated with NMTT-cephalosporins, whereas bleeding was not (OR 1.359, 95% CI 0.920–2.009). Subgroup analyses revealed that cefoperazone (OR 2.506, 95% CI 1.293–4.860), cefamandole (OR 3.247, 95% CI 1.083–9.733), and moxalactam (OR 3.367, 95% CI 1.725–6.572) were significantly associated with hypoprothrombinemia. An Antimicrobial Stewardship Program led by a multidisciplinary team could play a critical role in monitoring cephalosporin-related hypoprothrombinemia or PT prolongation in patients with underlying clinical conditions at risk for bleeding. The multidisciplinary team could also assist in communicating the potential safety concerns regarding NMTT-cephalosporin use with healthcare professionals to decrease the risk of adverse events.