New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials.

Objectives: This network meta-analysis aims to compare the efficacy and safety of new anti-diabetic medications for the treatment of non-alcoholic fatty liver disease (NAFLD). Materials and methods: PubMed and Scopus were searched from inception to 27th March 2022 to identify all randomized controlled trials (RCTs) in NAFLD patients. Outcomes included reductions in intrahepatic steatosis (IHS) and liver enzyme levels. The efficacy and safety of DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and other therapies were indirectly compared using a NMA approach. Unstandardized mean difference (USMD) with 95% confidence intervals (CI) were calculated. Results: 2,252 patients from 31 RCTs were included. "Add-on" GLP-1 agonists with standard of care (SoC) treatment showed significantly reduced IHS compared to SoC alone [USMD (95%CI) -3.93% (-6.54%, -1.33%)]. Surface under the cumulative ranking curve (SUCRA) identified GLP-1 receptor agonists with the highest probability to reduce IHS (SUCRA 88.5%), followed by DPP-4 inhibitors (SUCRA 69.6%) and pioglitazone (SUCRA 62.2%). "Add-on" GLP-1 receptor agonists were also the most effective treatment for reducing liver enzyme levels; AST [USMD of -5.04 (-8.46, -1.62)], ALT [USMD of -9.84 (-16.84, -2.85)] and GGT [USMD of -15.53 (-22.09, -8.97)] compared to SoC alone. However, GLP-1 agonists were most likely to be associated with an adverse event compared to other interventions. Conclusion: GLP-1 agonists may represent the most promising anti-diabetic treatment to reduce hepatic steatosis and liver enzyme activity in T2DM and NAFLD patients. Nevertheless, longer-term studies are required to determine whether this delays progression of liver cirrhosis in patients with NAFLD and T2DM. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021259336.1.

Injection of an improperly stored proprotein convertase subtilisin/kexin type 9 monoclonal antibody in a patient with secondary dyslipidemia from nephrotic syndrome: a case report.

BACKGROUND: Elevated plasma cholesterol and/or plasma triglyceride levels in nephrotic syndrome patients are the result of impaired lipoprotein clearance and a compensatory increase in hepatic lipoprotein synthesis. Plasma proprotein convertase subtilisin/kexin type 9 levels directly correlate to the amount of proteinuria in nephrotic syndrome patients. Proprotein convertase subtilisin/kexin type 9 monoclonal antibody has been used to treat dyslipidemia in some refractory nephrotic syndrome cases. As a therapeutic protein, proprotein convertase subtilisin/kexin type 9 monoclonal antibody simply deteriorates if stored in inappropriate temperatures or conditions. CASE PRESENTATION: In this article, we present the case of a 16-year-old Thai female with severe combined dyslipidemia secondary to refractory nephrotic syndrome. She received proprotein convertase subtilisin/kexin type 9 monoclonal antibody (alirocumab) treatment. However, the drugs were mistakenly frozen in a freezer for up to 17 hours before being stored at 4 °C. After using two frozen devices, serum total cholesterol, free proprotein convertase subtilisin/kexin type 9, and lipoprotein(a) significantly decreased. Nonetheless, the patient developed a skin rash 2 weeks after the second injection and the lesion spontaneously resolved without any treatment approximately 1 month later. CONCLUSIONS: The effectiveness of proprotein convertase subtilisin/kexin type 9 monoclonal antibody seems to be stable after being stored under freeze-thaw conditions. However, improperly stored drugs should be discarded to avoid any potential undesirable side effects.

Comparative cardiovascular benefits of individual SGLT2 inhibitors in type 2 diabetes and heart failure: a systematic review and network meta-analysis of randomized controlled trials.

Background: In patients with type 2 diabetes (T2D) and a history of heart failure (HF), sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated cardiovascular (CV) benefits. However, the comparative efficacy of individual SGLT2is remains uncertain. This network meta-analysis (NMA) compared the efficacy and safety of five SGLT2is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin) on CV outcomes in these patients. Materials and methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to September 23, 2022, to identify all randomized controlled trials (RCTs) comparing SGLT2is to placebo in T2D patients with HF. The main outcomes included composite CV death/heart failure hospitalization (HFH), HFH, CV death, all-cause mortality, and adverse events. Pairwise and NMA approaches were applied. Results: Our analysis included 11 RCTs with a total of 20,438 patients with T2D and HF. All SGLT2is significantly reduced HFH compared to standard of care (SoC) alone. "Add-on" SGLT2is, except ertugliflozin, significantly reduced composite CV death/HFH relative to SoC alone. Moreover, canagliflozin had lower composite CV death/HFH compared to dapagliflozin. Based on the surface under the cumulative ranking curve (SUCRA), the top-ranked SGLT2is for reducing HFH were canagliflozin (95.5%), sotagliflozin (66.0%), and empagliflozin (57.2%). Head-to-head comparisons found no significant differences between individual SGLT2is in reducing CV death. "Add-on" SGLT2is reduced all-cause mortality compared with SoC alone, although only dapagliflozin was statistically significant. No SGLT2is were significantly associated with serious adverse events. A sensitivity analysis focusing on HF-specific trials found that dapagliflozin, empagliflozin, and sotagliflozin significantly reduced composite CV death/HFH, consistent with the main analysis. However, no significant differences were identified from their head-to-head comparisons in the NMA. The SUCRA indicated that sotagliflozin had the highest probability of reducing composite CV death/HFH (97.6%), followed by empagliflozin (58.4%) and dapagliflozin (44.0%). Conclusion: SGLT2is significantly reduce the composite CV death/HFH outcome. Among them, canagliflozin may be considered the preferred treatment for patients with diabetes and a history of heart failure, but it may also be associated with an increased risk of any adverse events compared to other SGLT2is. However, a sensitivity analysis focusing on HF-specific trials identified sotagliflozin as the most likely agent to reduce CV death/HFH, followed by empagliflozin and dapagliflozin. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022353754.

The Effect of high temperature on the stability of basal insulin in a pen: a randomized controlled, crossover, equivalence trial.

INTRODUCTION: Insulin is an essential medicine in the management of diabetes. When stored at high temperatures(HTs), its efficacy could rapidly decline. Therefore, appropriate storage of in-use insulin is necessary to achieve its maximum therapeutic effects. However, the ambient temperature in tropical countries is normally relatively high. This study aimed to compare the efficacies of basal insulin in a pen previously kept at 37°C for 21 days and basal insulin in a refrigerated pen (2°C-8°C). Continuous glucose monitoring (CGM) was used to evaluate daily mean glucose levels (MGLs). RESEARCH DESIGN AND METHODS: This randomized controlled, crossover, equivalence trial recruited adults with type 2 diabetes mellitus and glycated hemoglobin levels <8% who had used insulin glargine for >3 months. Subjects were randomized for sequential use of refrigerated basal insulin followed by basal insulin kept at HT, with a 2-week washout between phases. The HT insulin pens were stored in a 37°C incubator for 21 days before use, while the refrigerated insulin pens were stored at 2°C-8°C. Study patients received 7-day CGM. The primary outcome was the difference in the groups' MGLs. The secondary outcome parameters were glucose variability represented by the standard deviation (SD), mean amplitude of glycemic excursion (MAGE), and percentage of time in range (TIR). The remaining quantity of insulin was evaluated by ultrahigh-performance liquid chromatography (UHPLC) assay. RESULTS: Forty patients completed the study. The MGLwas 158.7±30.5 mg/dL and 157.0±40.9 mg/dL in the HT and refrigerated insulin pen groups, respectively (p=0.72). The groups had no significant differences in MAGE7day, SD, percentage of TIR, carryover period, or treatment effects (all p>0.05). There was also no significant difference in the remaining quantity of insulin evaluated by UHPLC (p=0.97). CONCLUSIONS: HT basal insulin pens retain their potency and have biological activity comparable to that of refrigerated pens.Trial registration number TCTR20210611002.

A rare case of ectopic ACTH syndrome caused by primary renal neuroendocrine tumor.

SUMMARY: Ectopic adrenocorticotropic hormone (ACTH) secretion is responsible for 5-15% of Cushing's syndrome (CS). Neuroendocrine tumor (NET) is a common cause of ectopic ACTH syndrome (EAS). However, primary renal NET is exceedingly rare. Fewer than 100 cases have been reported and only a few cases presented with CS. Because of its rarity and lack of long-term follow-up data, clinical manifestations, biological behavior and prognosis are not well understood. Here, we report the case of a 51-year-old man who presented with clinical and laboratory findings compatible with EAS. CT scan revealed a lesion of uncertain nature at the lower pole of the left kidney. Octreotide scan found a filling defect at the lower pole of left kidney. It was difficult to determine if this finding was the true etiology or an incidental finding. Unfortunately, the patient's clinical status rapidly deteriorated with limited medical treatment. The patient underwent left nephrectomy and left adrenalectomy. Histopathological examination confirmed NET with oncocytic features. Immunohistochemistry staining was positive for ACTH. The patient's condition gradually improved. Additionally, glucocorticoid replacement was required only 6 months during a gradual recovery of hypothalamic pituitary adrenal axis achieved approximately three years after tumor removal. Although extremely rare, primary renal NET should be considered as a cause of EAS particularly in a patient with rapid clinical deterioration. Thorough investigation, early diagnosis and careful management are crucial to reduce morbidity and mortality. LEARNING POINTS: Primary renal NET is an extremely rare cause of ectopic ACTH syndrome. Ectopic ACTH syndrome has a rapid onset with severe clinical manifestations. In this case, the patient's condition deteriorated rapidly, resulting from severe hypercortisolism. Resection of the tumor is the most effective treatment. Localization of ectopic ACTH-secreting tumors is very challenging. Multimodality imaging including CT, MRI, octreotide scan, and positron emission tomography plays a crucial role in identifying the tumors. However, each imaging modality has limitations.

The effect of temperature on the stability of PCSK-9 monoclonal antibody: an experimental study.

BACKGROUND: PCSK9 monoclonal antibody lowers plasma PCSK9 and LDL-cholesterol levels. The manufacturers recommend drug storage at 2-8 °C, and not above 25 °C. This study aimed to investigate drug stability at various temperatures that this drug could be exposed to during medication handling and transportation in tropical countries. METHODS: Alirocumab and evolocumab were tested in 3 study conditions: room temperature (RT), cooler device with cold pack, and freeze-thaw for 9 and 18 h. Heated drugs were used as negative control. Free plasma PCSK9 levels from 9 hyperlipidemia subjects were measured with ELISA. RESULTS: Average subject age was 49.2 ± 18.4 years. Percent PCSK9 inhibition significantly declined in heated drugs compared to baseline. Average RT during the study period was 30.4 ±2.6 °C. Change in percent PCSK9 inhibition of PCSK9 mAb at RT from baseline was - 5.8 ± 4.4% (P = 0.005) and - 11.0 ± 8.9% (P = 0.006) for alirocumab at 9 h and 18 h, and - 9.7 ± 11.8% (P = 0.04) and - 15.1 ± 14.3% (P = 0.01) for evolocumab at 9 and 18 h, respectively. In contrast, there were no significant changes in percent PCSK9 inhibition from baseline when PCSK9 mAb was stored in a cooler. In freeze-thaw condition, changes in percent PCSK9 inhibition from baseline to 9 and 18 h were - 5.2 ± 2.9% (P = 0.001) and - 2.6 ± 4.9% (P = 0.16) for alirocumab, and - 1.8 ± 4.2% (P = 0.24) and 0.4 ± 6.1% (P = 0.83) for evolocumab. CONCLUSION: Proper drug storage according to manufacturer's recommendation is essential. Drug storage at RT in tropical climate for longer than 9 h significantly decreased drug efficacy; however, storage in a cooler device with cold pack for up to 18 h is safe.

The Effect of Temperature on the Stability of In-Use Insulin Pens.

BACKGROUND: Improper storage of insulin could decrease its potency. Manufacturers recommend that in-use insulin pens should be kept at between 25-30°C, but room temperature in tropical countries often exceeds this range. This study investigates the effect of temperature on the stability of basal insulin in cartridges 28 days after opening. METHODS: Four different basal insulins were evaluated. Five opened pens of each insulin type were included for each of three storage conditions and 5 unopened insulin pens of each type were stored in the refrigerator as a control. The opened pens were stored for 28 days in either a refrigerator (2-8 °C), at room temperature, or in an incubator (37 °C). Each day insulin pens were mixed 20 times and 2 units were discarded to mimic daily usage. Insulin quantity was evaluated using an ultra-high-performance liquid chromatography assay. RESULTS: The average room temperature during the study period was 29.7 °C. After 28 days, the percentage amount of insulin stored at refrigerator, room temperature or incubator, compared with control was 99.0, 99.7, 101.1% for long-acting insulin; 97.4, 97.2, 99.0% for NPH-1; 101.4, 101.5, 100.7% for NPH-2; and 98.7, 97.8, 98.5% for NPH-3. There were no statistically significant differences. However, we observed a trend toward different stability between clear insulin analog and turbid NPH insulin. CONCLUSIONS: Temperature as high as 37°C and cyclic temperature,had no effect on the stability of in-use insulin pen.