Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis.

BACKGROUND: Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. METHODS: We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized. RESULTS: Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]). CONCLUSIONS: In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

Camostat Mesilate, Pancrelipase, and Rabeprazole Combination Therapy Improves Epigastric Pain in Early Chronic Pancreatitis and Functional Dyspepsia with Pancreatic Enzyme Abnormalities.

BACKGROUND/AIMS: The aims of the study are to clarify the pathophysiological differences among early chronic pancreatitis (ECP), functional dyspepsia with pancreatic (FD-P) enzyme abnormalities and FD patients and to determine whether camostat mesilate, pancrelipase, and rabeprazole triple therapy improve FD symptoms in the ECP patients and FD-P patients in cross-over way. METHODS: We enrolled 84 consecutive patients presenting with typical symptoms of FD patients (n = 42), ECP patients (n = 15), and FD-P patients (n = 27). Gastric emptying was assessed by the 13C-acetate breath test. ECP was diagnosed based on the criteria recommended by the Japan Pancreatic Association. RESULTS: The proportions of female in ECP patients and FD-P were significantly higher compared to that in FD patients. The early phase of gastric emptying in ECP and FD-P patients was significantly disturbed compared to that in FD patients. The primary outcome of this study is that 4 weeks of camostat mesilate, pancrelipase, and rabeprazole triple therapy significantly ameliorated epigastric pain in ECP patients compared to acotiamide and rabeprazole combination therapy. CONCLUSION: Although there were no significant differences in pathophysiology between ECP patients and FD-P patients, triple therapy can significantly ameliorate epigastric pain in ECP patients. Further studies will be needed to clarify why triple therapy can improve epigastric pain in ECP patients.

Epigastric pain syndrome accompanying pancreatic enzyme abnormalities was overlapped with early chronic pancreatitis using endosonography.

There was not available data about the overlap between functional dyspepsia (FD) and pancreatic diseases. We aimed to determine whether epigastric pain syndrome (EPS) accompanying with pancreatic enzyme abnormalities were associated with early chronic pancreatitis proposed by Japan Pancreas Society (JPS) using endosonography. We enrolled 99 consecutive patients presenting with typical symptoms of FD, including patients with postprandial distress syndrome (PDS) (n = 59), EPS with pancreatic enzyme abnormalities (n = 41) and EPS without pancreatic enzyme abnormalities (n = 42) based on Rome III criteria. Gastric motility was evaluated using the 13C-acetate breath test. Early chronic pancreatitis was detected by endosonography and graded from 0 to 7. The ratio of female patients among EPS patients (34/41) with pancreatic enzyme abnormalities was significantly (p = 0.0018) higher than the ratio of female EPS patients (20/42) without it. Postprandial abdominal distention and physical component summary (PCS) scores in EPS patients with pancreatic enzyme abnormalities were significantly disturbed compared to those in EPS patients without it. Interestingly, AUC5 and AUC15 values (24.85 ± 1.31 and 56.11 ± 2.51, respectively) in EPS patients with pancreatic enzyme abnormalities were also significantly (p = 0.002 and p = 0.001, respectively) increased compared to those (19.75 ± 1.01 and 47.02 ± 1.99, respectively) in EPS patients without it. Overall, 64% of EPS patients with pancreatic enzyme abnormalities were diagnosed by endosonography as having concomitant early chronic pancreatitis proposed by JPS. Further studies are warranted to clarify how EPS patients with pancreatic enzyme abnormalities were associated with early chronic pancreatitis proposed by JPS.

Pancreatic Dysfunction and Duodenal Inflammatory Responses Coordinate with Refractory Epigastric Pain Including Functional Dyspepsia: A Narrative Review.

Some patients with functional dyspepsia (FD) have abnormalities in pancreatic enzymes and chronic pancreatitis. Since 2009, when the idea of early chronic pancreatitis (ECP) first emerged, the utility of endoscopic ultrasonography gained attention, as it can help identify early chronic pancreatitis in patients with dyspepsia. Although the symptoms associated with pancreatic enzyme abnormalities and pancreatic dysfunction overlap with those of dyspepsia, no available data explain the direct relationships and linkages between pancreatic dysfunction and dyspeptic symptoms. Disturbance of exocrine pancreatic enzyme function and reduction in pancreatic endocrine levels, such as insulin, may be associated with dyspeptic symptoms through impaired gastric emptying and duodenal inflammation. Some recent studies have examined the role of duodenal pathophysiology in gastric motility, bicarbonate secretion, and digestion. Because reduced bicarbonate secretion, which is caused by pancreatic dysfunction, leads to a failure to neutralize gastric acid in the proximal duodenum, impaired bicarbonate secretion in turn fails to protect the duodenal mucosa against gastric acid influx, thereby inducing duodenal inflammation. In addition, elevated trypsin levels might be associated in part with duodenal inflammatory responses through PAR2-related immunomodulatory cells. This review describes how duodenal inflammation might affect the pathogenesis of FD and examines whether pancreatic dysfunction is associated with FD through intestinal inflammation.

Coronavirus disease 2019 and asthma, allergic rhinitis: molecular mechanisms and host-environmental interactions.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19), a respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus), is a pandemic in over 120 countries worldwide. Risk factors for severe COVID-19 include older age, ethnicity, sex, comorbidities, and living conditions. Although asthmatics and those with allergies are susceptible to more severe outcomes to viral infections, interestingly, asthma has not been reported to be a major comorbidity of COVID-19. However, there are some conflicting reports on the impact of asthma on COVID-19. The underlying immunological and molecular mechanisms may explain at least in part these observations. Furthermore, environmental factors like air pollution that have detrimental effects on asthma and respiratory illnesses also have an impact on COVID-19. RECENT FINDINGS: Angiotensin-converting enzyme 2 (ACE2) is the receptor for the attachment and entry of SARS-CoV-2 into the host cells that is upregulated by Th1-mediated responses. In asthmatics, ACE2 gene expression is generally reduced and recent studies have shown a negative correlation between the levels of Th2 cytokines including IL-4, IL-5, and IL-13 in airway epithelial cells and other type 2 biomarkers with ACE2 expression. This may explain in part the potential protective role of asthma on COVID-19. Here, we review the relation of respiratory viral illnesses and asthma, the immune-molecular mechanisms of SARS-CoV-2 infection, the impact of asthma on COVID-19 and that of SARS-CoV-2 on asthma and allergic rhinitis, and the impact of environmental factors like air pollution on COVID-19. SUMMARY: Expression of ACE2 in airway epithelial cells in SARS-COV-2 is influenced by inflammatory profile. Respiratory allergic diseases like asthma appear to have a protective effect against SARS-COV-2 infection. However, the clinical association between asthma and SARS-COV-2 is not fully established and the underlying immune-molecular mechanisms may explain these observations.

Value of leukocytosis and elevated C-reactive protein in predicting severe coronavirus 2019 (COVID-19): A systematic review and meta-analysis.

BACKGROUND: Since December 2019, coronavirus 2019 (COVID-19) has spread worldwide. Identifying poor prognostic factors is helpful for risk stratification. In this meta-analysis, we investigated the association between severe COVID-19 and a change in white blood cell (WBC) count, an elevation of C-reactive protein (CRP), and fever. Moreover, we aimed to evaluate the diagnostic accuracy of leukocytosis and an elevation of CRP. METHODS: We performed a systematic search of PubMed, EMBASE, Scopus, and the Cochrane Library through April 20th, 2020. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A sensitivity analysis was conducted according to the study size (>200 or <200) and median age (>55 or <55). Meta-regression analyses were conducted to examine possible sources of heterogeneity. We calculated the diagnostic accuracy of leukocytosis and CRP. RESULTS: Eighteen studies with 3278 patients were selected. Fever, leukocytosis, and elevated CRP were associated with poor outcomes (OR (95% CI) 1.63 (1.06-2.51), 4.51 (2.53-8.04), and 11.97 (4.97-28.8), respectively). Leukopenia was associated with a better prognosis (OR 0.56, 95% CI 0.40-0.78). Sensitivity analyses showed similar tendencies. Meta-regression analysis for leukocytosis indicated that age, dyspnea, and hypertension contributed to heterogeneity. The pooled area under the leukocytosis and CRP curves were 0.70 (0.64-0.76) and 0.89 (0.80-0.99), respectively. CONCLUSION: In patients with COVID-19, fever, leukocytosis, and an elevated CRP were associated with severe outcomes. Leukocytosis and CRP on arrival may predict poor outcomes.

Management of functional dyspepsia: state of the art and emerging therapies.

Patients with functional dyspepsia, defined in the 2016 Rome IV criteria as bothersome clinical dyspepsia symptoms, experience markedly reduced quality of life. Several etiologies have been associated with the disorder. In the Rome IV criteria, the brain-gut axis was acknowledged as an important factor in the etiology of functional gastrointestinal (GI) disorders. The distinct subgroups of functional dyspepsia, epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS), are treated differently: acid secretion inhibitors are recommended with patients with EPS, whereas prokinetic drugs as mosapride and acotiamide are recommended for patients with PDS. A previous study has reported that proton pump inhibitors (PPIs) and H2-blockers were equally effective in functional dyspepsia. A new drug, acotiamide, a muscarinic antagonist and cholinesterase inhibitor, has been shown to improve gastric motility in rodents and dogs, and to reduce PDS symptoms in patients in double-blind multicenter studies. The pharmacological mechanisms of acotiamide remain unknown; whether acotiamide alters gastric emptying and gastric accommodation in patients with functional dyspepsia remains an open question. Other emerging treatment options include Rikkunshito, a herbal medicine that improves gastric emptying through 5-hydroxytryptamine (5-HT)2B-mediated pharmacological action, and tricyclic antidepressants (TCAs). Different drugs are needed to accommodate the clinical symptoms and etiology in individual patients.

Comparison of clinical symptoms, gastric motility and fat intake in the early chronic pancreatitis patients with anti-acid therapy-resistant functional dyspepsia patients.

BACKGROUND: There was no available data concerning the clinical differentiation between the updated definition of early chronic pancreatitis (ECP) and anti-acid therapy-resistant functional dyspepsia (RFD). AIMS: We aimed to determine whether clinical symptoms, gastric motility, psychogenic factors and fat intake can help distinguish early chronic pancreatitis (ECP) from anti-acid therapy-resistant functional dyspepsia patients with pancreatic enzyme abnormalities (RFD-P) and anti-acid therapy-resistant functional dyspepsia (RFD) patients using endosonography. METHODS: We enrolled 102 consecutive patients presenting with typical symptoms of RFD patients (n = 52), ECP patients (n = 25) and RFD-P patients (n = 25). ECP patients were diagnosed based on the criteria recommended by the Japan Pancreatic Association. Gastric motility was evaluated by 13C-acetate breath tests. Severity of duodenal inflammation was examined. RESULTS: 24.5% of RFD patients were determined as ECP using endosonography. Abdominal pain score in Gastrointestinal Symptom Rating Scale (GSRS) in the patients with ECP was significantly lower compared to that in the patients with RFD-P. There were no significant differences in State-Trait Inventory (STAI)-state/-trait scores, Self-Rating Questionnaire for Depression (SRQ-D) scores and clinical symptoms for fat intake among three groups. The early phase of gastric emptying (AUC5; AUC15) in ECP and RFD-P patients were significantly disturbed compared to those in RFD patients. CONCLUSIONS: Evaluation of severity of abdominal pain and measurement of the early phase of gastric emptying will be useful tools to distinguish ECP patients from RFD patients. Accurate diagnosis of ECP patients may contribute to the prevention from advancing of chronic pancreatitis.