Evaluación farmacológica del extracto de Raíz de rhazya stricta

The purpose of this study was to characterize neuropeptide Y (NPY) overflow and metabolism from isolated skeletal muscle arterioles of female rats. Gastrocnemius first-order arterioles were removed from young (2 months), young adult (6 months) and middle-aged (12 months) F344 female rats. Arterioles were isolated, cannulated and pressurized in a microvessel bath with field stimulation electrodes. NPY overflow from isolated arterioles was assessed at 0 s and 30 s post-field stimulation. Dipeptidyl peptidase IV (DPPIV) activity was quantified via fluorometric assay of whole vessel homogenate. In young adult and middle-aged rats, NPY overflow increased 0 s and 30 s following field stimulation. In young adult rats, DPPIV inhibition resulted in an increase in NPY overflow at 30 s, while middle-aged rats had no increase in NPY overflow with DPPIV inhibition (P <0.05). DPPIV activity was influenced by factors such as age, vessel type, and endothelium (P <0.05). The present data suggest that DPPIV plays a significant role in modulating the actions of NPY in arterioles of young adult females; however, this role appears to diminish with age.

The global epidemic of type 2 diabetes mellitus (T2DM) has substantial implications for cardiovascular disease–related morbidity and mortality.1 The prevalence of T2DM in patients with heart failure (HF) is high, with strong and independent association between T2DM and incident HF observed in multiple prospective studies and in randomized-controlled clinical trials. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled subject’s ≥55 years of age with hypertension and ≥1 risk factor, patients with T2DM had a 2-fold risk for HF hospitalization or death after adjustment for other risk factors (RR, 1.95). The association with T2DM was independent of coronary artery disease and at least equivalent in magnitude and greater than that for electrocardiographic left ventricular (LV) hypertrophy.2 All measures of glycemia including fasting, postprandial, measures of insulin resistance, and hemoglobin A1c (HbA1c) have been associated with risk of developing HF, with the association extending to both HF with preserved ejection fraction and to HF with reduced ejection fraction.3,4 A substantial body of evidence from preclinical studies, endomyocardial biopsies in humans and more recently with cardiac MRI, support increased myocardial stiffness in T2DM related to alteration in extracellular matrix. There are multiple proximate mediators that have been hypothesized to play a role including advanced glycation end product deposition and reactive oxygen species that may increase myocardial stiffness during diastole, by cross-linking collagen or by enhancing collagen formation.5,6 Another pernicious proximal mediator is the elevation in postprandial lipids, such as remnant lipoproteins, characteristic of atherogenic dyslipidemia, a highly prevalent abnormality in T2DM, that may result in direct myocellular deposition of lipid, leading to microcirculatory dysfunction, alteration in substrate use and mitochondrial dysfunction.7,8 Indeed, positron emission tomography studies show reduced myocardial glucose uptake in favor of fatty acid …

BackgroundDiabetes mellitus is a chronic disease characterized by hyperglycemia that may occur due to genetic, environmental or lifestyle factors. Natural remedies have been used to treat diabetes since long and many antidiabetic compounds of varied efficacies have been isolated from medicinal plants. Rhazya stricta has been used for decades for the treatment of diabetes mellitus and associated ailments. Considering the folkloric use of R. stricta against diabetes, it was aimed to investigate the effectiveness of its root extracts against diabetes through in vitro assays and in vivo studies using animal model along with phytochemical profiling through GCMS.MethodsVarious fractions of Rhazya stricta obtained through column chromatography were evaluated for a variety of assays including α-glucosidase, Dipeptidyl peptidase-IV (DPP-IV), β-secretase and Glucagon-like peptide-1 (GLP-1) secretion studies. For the in vivo studies the alloxan-induced diabetic mice were treated with root extracts and blood glucose levels, HbA1C, and other biochemical markers along with the histological study of the liver were done. The phytochemical identification was performed using an Agilent 7890B GC coupled to a 7010 Triple Quadrupole (MS/MS) system. GraphPad Prism software version 5.01 was used for statistical analysis.ResultsMajority of the extract fractions showed excellent results against diabetes by inhibiting enzymes DPP-IV (Up to 61%) and β-secretase (Up to 83%) with IC50s 979 μg/ml and 169 μg/ml respectively with increase in the GLP1 secretion. The results of in vivo studies indicated a marked reduction in blood glucose and HbA1c levels along with positive effects on other parameters like lipid profile, liver functions and renal functions of extract-treated mice as compared to control. The histological examination of the liver demonstrated hepatoprotective effects against diabetes led changes and various classes of phytochemicals were also identified through GCMS in different fractions.ConclusionThe results revealed strong antidiabetic activity of R. stricta root with the potential to protect body organs against diabetic changes. Moreover, a variety of phytochemicals has also been identified through GCMS that might be responsible for the antidiabetic potential of Rhazya stricta root.Graphical abstract

BackgroundOxidative stress and analgesia are connected with different pathological conditions. The drug candidates from synthetic sources are associated with various side effects; therefore, researchers are giving priority to find novel, effective and safe phytomedicines. Teucrium species possesses antioxidant, analgesic, anti-inflammatory and hepatoprotective activities. The essential oils of Teucrium stocksianum have shown strong antinociceptive potential. Our current study is designed to embark total phenolic content (TPC), antioxidant and antinociceptive potential of the methanolic extract of Teucrium stocksianum (METS).MethodPhytochemical composition was determined by using standard methods. Free radical scavenging potential and TPC of METS were assessed by using 2, 2-diphenyl-1-picryl-hydrazyl (DPPH) and Folin-Ciocalteu Reagent (FCR) respectively. Antinociceptive potential was determined by acetic acid induced abdominal writhing, formalin induced paw licking and tail immersion tests. Different test dose 50, 100 and 150 mg/kg body weight of METS were administered intra peritonealy (i.p) to various groups of mice for the evaluation of analgesic potential.ResultsPhytochemical screening confirmed the presence of flavonoids, tannins, saponins, anthraquinone, steroid, phlobatannin, terpenoid, glycoside and reducing sugars. METS was found safe at a dose of 1000 mg/kg body weight. A concentration dependent free radical scavenging effect was observed with methanolic aerial parts extract of Teucrium stocksianum (MAPETS) and methanolic roots extracts of Teucrium stocksianum (MRETS). MAPETS and MRETS have shown highest antioxidant activity 91.72% and 86.19% respectively at 100 μg/ml. MAPETS was found more rich (115.32 mg of GAE/g of dry material) in TPC as compared to MAPETS (105.41 mg of GAE/g). METS demonstrated a dose dependent antinociceptive potential in different pain models, like in acetic acid, formalin and tail immersion showing 83.103%, 80.872% and 67.58% at a dose of 150 mg/kg, similar to acetylsalicylic acid (74.79%, 82.87%, 100 mg/kg) and TramadolR (74%, 30 mg/kg) respectively.ConclusionStrong antioxidant potential and high TPCs are residing in the methanolic extract of T. stocksianum. METS showed analgesic potential in all models of nociception implying that both peripheral and central pathways of analgesia are involved. This might be due to the presence of various classes of phytochemicals in the plant extract.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome (MERS-CoV), which cause acute respiratory distress syndrome and case fatalities. COVID-19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS-CoV binds to the metalloprotease angiotensin-converting enzyme 2 (ACE2), MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane-bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID-19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID-19 disease severity, which creates interest regarding the use of gliptins in management of COVID-19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS-CoV-2.

Registration:PROSPERO: CRD42020210645Introduction:We aimed to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older patients with type 2 diabetes with inadequate glycaemic control.Methods:We included randomized controlled trials (RCTs) in older (⩾65 years) patients with type 2 diabetes. The intervention group was randomized to treatment with any DPP-4 inhibitors. A systematic search in MEDLINE and Embase was performed in December 2020. For assessing the risk of bias, RoB 2 tool was applied. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We pooled outcomes using random effects meta-analyses.Results:We identified 16 RCTs that included 19,317 patients with a mean age of greater than 70 years. The mean HbA1c level ranged between 7.1 and 10.0 g/dl. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly [risk ratio (RR) 1.04; 95% confidence interval (CI) 0.89–1.21]. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia (RR 1.08; 95% CI 1.01–1.16), but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas (RR 0.88; 95% CI 0.75–1.04). DPP-4 inhibitors probably reduce the risk for hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase hypoglycaemia risk. Second-line therapy in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case second-line treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.Plain language summarySafety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetesIntroduction:We performed the review to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older type 2 diabetes patients with blood sugar outside the normal level.Methods:To answer the question, we searched various electronic databases. We included studies in older (⩾65 years) patients with type 2 diabetes that assessed the safety of DPP-4 inhibitors. The data from the different studies were quantitatively summarized using statistical methods. We assessed the quality of the data to judge the certainty of the findings.Results:We identified 16 studies that included 19,317 patients with a mean age greater than 70 years. The average blood sugar level of patients in the included studies was slightly or moderately increased. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia, but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas. DPP-4s probably reduce the risk of hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase the risk that blood sugar falls below normal. Adding DPP-4 inhibitorss to standard care in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case additional treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.

Context: Uncaria sclerophylla (W.Hunter) Roxb., a traditional antidiabetic drug for Kalimantan people, has never been scientifically reported as an antidiabetic agent, especially in dipeptidyl peptidase-4 (DPP-4) inhibition and as an antioxidant. Aims: To identify the leaf's extract most active chromatographic fraction in DPP-4 inhibition and as an antioxidant and determine the compounds contained. Methods: Extraction was carried out using the four-grade maceration method, fractionation used column chromatography techniques, and bioassay used spectrofluorometric principles. Compound profiling was performed using liquid chromatography combined with electrospray ionization and quadrupole time-of-flight mass spectrometry (UPLC-ESI-QToF-MS/MS), and molecular docking was used to investigate interactions between major compounds and DPP-4. Results: This study highlights the potential of methanol leaf extract as an antidiabetic agent with a DPP-4 inhibition mechanism (IC50: 79.67 ± 2.95 µg/mL) and antioxidant mechanism with EC50 value of 9.50 ± 0.319 µg/mL (FRAP method) and 9.94 ± 0.1572 µg/mL (DPPH method). The methanol extract of the leaves has been proven to produce the best chromatographic fraction (FMet5) as a DPP-4 enzyme inhibitor agent, with an IC50 value of 50.71 ± 1.22 µg/mL, and as an antioxidant, with an EC50 value of 8.89 ± 0.1701 µg/mL (FRAP method) and 6.07 ± 0.125 µg/mL (DPPH method). UPLC-ESI-QToF-MS/MS profiling of the compounds in FMet5 revealed the presence of various alkaloid and flavonoid compounds like dehydrosilybin, 19-epi-3-isoajmalicine, procyanidin A2, cinchonain I b, maokonine, and cuscohygrine. Conclusions: Extracts and chromatographic fractions derived from the leaves of U. sclerophylla have potent antioxidant and DPP-4 inhibitory properties, indicating their potential as an antidiabetic agent with DPP-4 inhibition and antioxidant mechanisms.

To the Editor: Incretin-based therapies for type 2 diabetes mellitus (T2DM) include incretin mimetics of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and incretin enhancers of dipeptidyl peptidase-4 (DPP-4) inhibitors.[1] With good hypoglycemic effects of incretin-based drugs that show no weight gain or hypoglycemia risk, these drugs are increasingly used in patients with T2DM. GLP-1 RAs are considered superior to DPP-4 inhibitors in controlling glycosylated hemoglobin, fasting blood glucose, and body weight.[2] However, the incidence of adverse events, such as adverse gastrointestinal reactions and dizziness caused by GLP-1 RAs, is higher than it is for DPP-4 inhibitors.[3] Unlike other anti-diabetic agents, safety concerns have been raised regarding the risk for gastrointestinal cancer associated with incretin-based treatments. Both a better understanding of their roles as second-line glucose-lowering treatments and a comprehensive assessment of their benefits and harms could inform the choice of treatment in clinical practice. Multicriteria decision analysis (MCDA), a general framework for constructing multicriteria decision models for benefit-risk assessment (BRA), has been widely used in health management and drug evaluation.[4,5] The stochastic multicriteria acceptability analysis (SMAA) model was developed from the traditional MCDA model to reduce the impact of the value preferences of decision-makers without requiring them to give subjective weight to decision-making indicators.[6,7] Previous studies have reviewed the multiple benefit and risk outcomes of GLP-1 RAs and DPP-4 inhibitors, but none have adopted the BRA evaluation model to synthesize multiple outcomes and obtain comprehensive comparison results. In this study, SMAA and network meta-analysis (NMA) were used to analyze the BRA of incretin-based treatments with other anti-diabetic agents to provide more comprehensive evidence for the clinical use of anti-diabetic agents in the treatment of T2DM. The risk/benefit outcomes were identified through reference to previous reviews, NMA, and drug information published by the Food and Drug Administration on incretin-based therapies. These included 26 outcomes, as shown in Figure 1 and Supplementary Table 1, https://links.lww.com/CM9/B446. Medline, Embase, ClinicalTrials.gov, and the Cochrane Library were searched from their inception to March 29, 2019. We used "Glucagon-Like Peptide-1 Receptors" and "Dipeptidyl-Peptidase IV Inhibitors" as keywords or MeSH terms, accompanied by EMTREE terms and relevant free words to search these databases.Figure 1: Value map of the BRA index of incretin-based therapies. Network plot presenting the trial data contributing evidence comparing incretin-based therapies for outcomes. (A) FPG, HbA1c, PPG, weight; (B) HDL, LDL, TC, TG; (C) DBP, heart rate, SBP; (D) Constipation, diarrhea, dyspepsia, gastroenteritis, nausea, vomiting; (E) All-cause death, hypertension, hypoglycemia, MACE, pancreatitis; (F) Arthralgia, cancers of digestive system, dizziness, headache. AGI: Alpha-glucosidase inhibitor; BRA: Benefit-risk assessment; DBP: Diastolic blood pressure; DPP-4: Dipeptidyl peptidase-4; FPG: Fasting plasma glucose; GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; HbA1c: Glycosylated hemoglobin; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; MACE: Major adverse cardiovascular events; Met: Metformin; PPG: Postprandial plasma glucose; SBP: Systolic blood pressure; SGLT-2: Sodium-glucose co-transporter 2; SU: Sulfonylureas; TC: Total cholesterol; TG: Triglyceride; TZD: Thiazolidinediones.The inclusion criteria were as follows: (1) reports written in English; (2) randomized clinical trials (RCTs); (3) the subjects were T2DM; (4) the intervention measures were GLP-1 RAs or DPP-4 inhibitors; (5) metformin (Met), sulfonylureas (SU), thiazolidinediones (TZD), alpha-glucosidase inhibitor (AGI), sodium-glucose co-transporter 2 (SGLT-2) inhibitor, insulin, or placebo as control measures; (6) GLP-1 RAs and DPP-4 inhibitors as control drugs; and (7) relevant indicators appearing in the study are included in the literature. Exclusion criteria were as follows: (1) reports not written in English; (2) non-RCTs; (3) the subjects were not T2DM; (4) animal research and other basic research; (5) no GLP-1 RAs and DPP-4 inhibitors in the intervention; and (6) ongoing or unfinished experimental studies. Data were extracted, including trial information (author, title, publication year, sample size, trial duration, types of intervention, and control), population characteristics (diabetes duration, age, baseline level of glycosylated hemoglobin A1c (HbA1c), background treatment), types of intervention and control measures, benefit and risk indicators, and relevant results. Two investigators (FS and SBC) extracted data independently in duplicate. The quality of studies was assessed using the Cochrane risk of bias tool (generation of random sequence, allocation hidden, blind method of the research object, results blind method, data integrity, selective reporting, and funded by company randomization). The Bayesian method was used to analyze each risk/benefit outcome. The measure of each risk/benefit outcome indicator was expressed as mean difference or odds ratio and its 95% confidence interval. The first main result of SMAA was acceptability, that is the probability of the scheme ranking in the evaluation system. The second main result was the confidence factor (CF). This refers to the probability that the alternatives rank first when the central weight vector is selected. Based on SMAA, the results of inconsistent comparison pairs in the NMA results were replaced with the direct comparison of the results of the meta-analysis, and indicators that could be related to each other in the outcome indicators were removed for sensitivity to test the stability of the model results. Of the 26 related BRA outcomes [Figure 1 and Supplementary Table 1, https://links.lww.com/CM9/B446], 11 were benefit indicators, including glycosylated HbA1c, fasting plasma glucose, postprandial plasma glucose, weight, blood lipids, blood pressure, and heart rate. In all, 15 were risk indicators, including all-cause death, pancreatitis, constipation, diarrhea, dyspepsia, gastroenteritis, nausea, vomiting, arthralgia, hypertension, cancers of the digestive system, dizziness, headache, hypoglycemia, and major adverse cardiovascular events. A total of 589 RCTs involving 295,908 patients with T2DM were included. In all, 34 RCTs (16,023 patients with T2DM) on GLP-1 RAs and DPP-4 inhibitors were head-to-head comparisons. In other comparisons, comparators included metformin, SU, TZD, AGI, SGLT-2 inhibitors, insulin, and placebo. The overall quality of the literature is high, except for the high risk associated with the research object, the use of blind methods of outcome evaluation, and corporate sponsorship. We compared the effects of DPP-4 inhibitors and GLP-1 RAs on benefit and risk indicators, respectively. The effects of incretin and insulin, Met, SGLT-2 inhibitors, SU, TZD, and AGI on the benefit and risk indicators were also compared. The acceptability of GLP-1 RAs was better than that of DPP-4 inhibitors in 84.5% of cases. The CF for GLP-1 RAs being better than DPP-4 inhibitors was 99.5%. The acceptability of DPP-4 inhibitors was better than that of insulin in 93.1% of cases, and that of GLP-1 RAs were better than insulin in 90.6% of cases. The CF for DPP-4 inhibitors being better than insulin was 99.5%, and for GLP-1 RAs being better than insulin was 99.9%. The acceptability of Met was better than that of DPP-4 inhibitors in 61.5% of cases, and that of GLP-1 RAs were better than Met in 70.4% of cases. The CF for Met being better than DPP-4 inhibitors was 88.7%, and for GLP-1 RAs being better than Met was 92.2%. The acceptability of SGLT-2 inhibitors was better than that of DPP-4 inhibitors in 93.5% of cases, and that of SGLT-2 inhibitors was better than that of GLP-1 RAs in 76.0% of cases. The CF for SGLT-2 inhibitors being better than DPP-4 inhibitors was 99.7%, and for SGLT-2 inhibitors being better than GLP-1 RAs was 92.9%. The acceptability of DPP-4 inhibitors was better than that of SU in 80.4% of cases, and that of GLP-1 RAs was better than that of SU in 94.2% of cases. The CF for DPP-4 inhibitors being better than SU was 96.4%, and for GLP-1 RAs being better than SU was 99.9%. The acceptability of TZD was better than that of DPP-4 inhibitors in 58.6% of cases, and that of GLP-1 RAs was better than that of TZD in 69.8% of cases. The CF for TZD being better than DPP-4 inhibitors was 90.9%, and that for GLP-1 RAs being better than TZD was 97.1%. The acceptability of DPP-4 inhibitors was better than that of AGI in 72.1% of cases, and that of GLP-1 RAs was better than that of AGI in 89.4% of cases. The CF for DPP-4 inhibitors being better than AGI was 84.6%, and that for GLP-1 RAs being better than AGI was 98.9%. Based on SMAA, GLP-1 RAs were more likely to be superior to DPP-4 inhibitors in terms of BRA. The acceptability of GLP-1 RAs was better than those of insulin, SU, TZD, and AGI but lower than that of SGLT-2 inhibitors. The acceptability of DPP-4 inhibitors was higher than those of insulin and SU but lower than that of Met and SGLT-2 inhibitors. SMAA is a derivative model of MCDA, which is widely used in various industries. As it is presently used in the medical field, MCDA has eight steps: clarifying the decision-making environment, determining the evaluation index, collecting the specific data from each index, normalizing the data collected by each index, giving each index weight, calculating BRA values, conducting sensitivity analyses, and interpreting the results. Unlike the traditional MCDA model, SMAA reduces the impact of the value preferences of evaluators on decision-making and does not need decision-makers to give subjective weight to decision-making indicators. This study had many advantages. First, a total of 589 RCT studies involving 295,908 patients with T2DM were systematically searched and included in it. The sample size was large, and the bias risk for each study was evaluated. Second, 26 risk/benefit outcome indicators related to the treatment of T2DM with incretin were included, and the indicators were comprehensive and representative. Third, the SMAA model used in this study can reduce the subjectivity of decision-makers as they weight the indicators, at least to a certain extent. Further analysis regarding patient-level characteristics and their values and preferences are warranted (Supplementary Link: https://links.lww.com/CM9/B369). (Table 1) Table 1 - Results of SMAA analysis. Drug name Rank acceptability index (%) CF (%) GLP-1 RAs-DPP-4 inhibitors 84.5 99.5 DPP-4 inhibitors-insulin 93.1 99.5 GLP-1 RAs-insulin 90.6 99.9 Met-DPP-4 inhibitors 61.5 88.7 GLP-1 RAs-Met 70.4 92.2 SGLT-2 inhibitors-DPP-4 inhibitors 93.5 99.7 SGLT-2 inhibitors-GLP-1 RAs 76.0 92.9 DPP-4 inhibitors-SU 80.4 96.4 GLP-1 RAs-SU 94.2 99.9 TZD-DPP-4 inhibitors 58.6 90.9 GLP-1 RAs-TZD 69.8 97.1 DPP-4 inhibitors-AGI 72.1 84.6 GLP-1 RAs-AGI 89.4 98.9 AGI: Alpha-glucosidase inhibitor; CF: Confidence factor; DPP-4: Dipeptidyl peptidase-4; GLP-1 Ras: Glucagon-like peptide-1 receptor agonists; Met: Metformin; SGLT-2: Sodium-glucose co-transporter 2; SMAA: Stochastic multi-criteria acceptability analysis; SU: Sulfonylureas; TZD: Thiazolidinediones. Funding This work was supported by a grant from the National Natural Science Foundation of China (No. 72074011). Conflicts of interest None.

Heart failure is a major co-morbid association of diabetes mellitus. The incidence of heart failure in diabetic vs. control subjects is 2- to 3-fold greater in every decade of life.1 Similar data on prevalence have also been observed in the Framingham study.2 Conversely, diabetes represents a major co-morbidity in patients with heart failure. In both clinical trials and registries of heart failure patients, between 24% and 44% have known diabetes mellitus.3 A key epidemiological issue in the context of discussion of therapies for diabetes and the associated risk of heart failure is the impact of glycaemic control on heart failure risk. Both UKPDS4 and a large cohort investigated by Iribarren et al.5 have demonstrated a close positive linear relationship between haemoglobin A1c levels and rate of heart failure development. Specifically, poorest glycaemic control was associated with greatest risk of heart failure. However, studies such as UKPDS demonstrated that more intensive glycaemic control was not associated with reduced development of heart failure.6 More contemporaneous meta-analyses have supported this observation,7 albeit potentially driven by drug treatments such as thiazolidinediones which may contribute to heart failure development. Based on pre-clinical and early clinical work, dipeptidyl peptidase-4 (DPP-4) inhibitors should, in theory, have beneficial rather than adverse effects on progression of LV remodelling and therefore delay development of symptomatic heart failure8 (Figure 1). Dipeptidyl peptidase-4 is involved in the enzymatic breakdown of glucagon-like peptide (GLP)-1; thus, DPP-4 inhibition augments circulating GLP-1 levels, which appears to have beneficial effects upon the heart in animal models as well as in the post-myocardial infarction and established heart failure settings in man.9 DPP-4 stimulates activation of proinflammatory cytokines,9 independent drivers of progression of LV systolic dysfunction due to their prohypertrophic and profibrotic effects.10 Inhibition of DPP-4 augments circulating levels of soluble-derived factor (SDF)-1 α,9 a stimulant of bone marrow production of erythroid precursor cells, which should contribute to improved vascular and myocardial function. Finally, DPP-4 inhibition should direct BNP metabolism towards an increase in active BNP rather than biologically inactive BNP precursor fragments.9 Pre-clinical studies with DPP-4 inhibitors in animal models of LV systolic dysfunction11 support a beneficial effect on LV remodelling and survival in comparison with controls. Published and ongoing major cardiovascular outcome trials with DPP-4 inhibitors are summarized in Table 1. Three major DPP-4 inhibitor trials have recently reported, all with implications for heart failure, and these are examined in greater detail below. The SAVOR-TIMI 53 trial compared the DPP-4 inhibitor, saxagliptin, with placebo in the setting of patients with a history of, or who are at risk of, cardiovascular events.12 There was no overall effect of saxagliptin vs. placebo on the primary endpoint of time to first event of cardiovascular death, myocardial infarction, or ischaemic stroke. However, patients in the saxagliptin group were more likely to be hospitalized for heart failure than those in the placebo group [3.5 vs. 2.8%, hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.07–1.51, P = 0.007]. A Kaplan–Meier plot of accrual of heart failure hospitalizations over time showed an early divergence of the curves which continued to diverge slightly beyond the first 180 days of treatment.13 A Forrest plot of key baseline variables that may influence risk of heart failure hospitalization according to treatment did not demonstrate any heterogeneity, with all pre-defined subgroups trending towards an excess of primary endpoint events with saxagliptin vs. placebo. One exception may be baseline plasma NT-proBNP levels. In those patients within the highest BNP quartile (333–46627 pg/mL), 10.9% of saxagliptin and 8.9% of placebo patients had a hospitalization for heart failure (P = 0.024). The EXAMINE study assessed the DPP-4 inhibitor, alogliptin, in patients who had recently had an acute coronary syndrome.14 As with saxagliptin in SAVOR, there was no significant effect of this class on the primary endpoint (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke). In EXAMINE, 3.9% of alogliptin-treated and 3.3% of placebo-treated patients had a hospitalization for heart failure (HR 1.19, 95% CI 0.89–1.58, P = NS).15 This was a pre-defined exploratory endpoint that was independently adjudicated. In EXAMINE, 28% of patients had a history of congestive heart failure at baseline. The primary EXAMINE endpoint was reduced with alogliptin vs. placebo, HR 0.82, P = 0.2015, in these patients. Data on recurrent heart failure hospitalizations within this subgroup have not as yet been reported. The Vildagliptin In Ventricular Dysfunction Diabetes (VIVIDD) trial has been presented16 but not yet published. All patients in VIVIDD had evidence of symptomatic systolic heart failure with an LVEF <35% as well as diabetes requiring glucose-lowering therapy. There was no difference in adjudicated heart failure events between vildagliptin (n = 128, 18%) and placebo (n = 125, 17.6%) patients over the 52 weeks of the study. The primary endpoint of the VIVIDD study was change in LVEF, with no difference observed between treatment groups (+0.54, 95% CI –1.97 to 3.06, P = 0.67). Interestingly, plasma BNP levels were reduced in both groups: vildagliptin, ratio of 0.72 vs. baseline; placebo, 0.86 vs. baseline. Somewhat surprisingly, LV diastolic and systolic volumes were both increased with vildagliptin compared with placebo. Our group recently performed a meta-analysis of heart failure outcomes with DPP-4 inhibitors, including the above studies. Forest plots of these data, comparing DPP-4 inhibitor with placebo and an active comparator, are shown in Figure 2. A sensitivity analysis was also undertaken, with thiazolidenediones included and excluded as comparator. With thiazolidenediones included, the risk ratio for heart failure with DPP-4 inhibitors was 0.80, 95% CI 0.35–1.81, P = 0.59. With thiazolidenediones removed as comparator, the risk ratio for heart failure was 1.15, 95% CI 1.00–1.33, P = 0.04. It is not entirely certain whether DPP-4 inhibitors directly or even indirectly cause heart failure, but if one accepts the premise that this is the case, then a number of potential explanations need to be considered. It is entirely plausible that the increase in heart failure events observed, particularly in SAVOR,12 represents the play of chance. There is a long history of ‘play of chance’ influencing cardiovascular trials. This is particularly true of subgroup analysis, but would equally apply to analysis of ‘off-target’ effects of drugs.17 Nevertheless, there are hints with DPP-4 inhibitors that this may not be the case, especially given the numerical increase in events in EXAMINE14 and the odd remodelling effects of vildagliptin in VIVIDD.16 Furthermore, there was an excess (not significant) of all-cause mortality events with vildagliptin amongst patients in VIVIDD.24 Although SAVOR and EXAMINE were large trials and baseline characteristics appear to be well balanced, it is certainly possible that there were imbalances at baseline between groups, which may have led to an increase in risk of heart failure hospitalization with the DPP-4 inhibitor. Specifically, there may be imbalances in background medications that are known to retard heart failure progression, such as ACE inhibitors. It would certainly be prudent to look at the patients who did have a heart failure hospitalization to see if there are baseline imbalances within this specific subgroup. Hypoglycaemia stimulates the sympathetic and renin–angiotensin–aldosterone systems and, thus, with chronic stimulation, may have adverse consequences including progression to symptomatic heart failure. However, the increase in rates of hypoglycaemia in both SAVOR and EXAMINE were very modest compared with the placebo group. An increase in relative risk for hypoglycaemia with saxagliptin in SAVOR was noted in patients on background sulfonylureas.12 However, when this subgroup was examined, there was no increase in risk of heart failure hospitalization with saxagliptin.13 Similarly, in EXAMINE, differences in hypoglycaemia were very minor between the alogliptin and placebo groups.14 Marney et al.18 suggested that sitagliptin interacted with high-dose enalapril to increase rather than decrease blood pressure levels in metabolic syndrome patients. This was associated with an increase in heart rate and plasma norepinephrine levels that was significant at the highest dose of enalapril. The mechanisms underlying this interaction are unclear but may relate to blockade of the peptides substance P and/or neuropeptide Y with DPP-4 inhibitors, leading to sympathetically mediated vasoconstriction. Similarly, Jackson et al.19 demonstrated that, in a renal perfusion model, enhancement of angiotensin II-mediated constrictor responses due to increasing neuropeptide Y administration could be exacerbated by sitagliptin and blocked if sitagliptin is given with a neuropeptide Y inhibitor. If the above are correct, then attention to heart rate and blood pressure responses in the major DPP-4 outcome trials would be of considerable interest. However, an analysis of earlier, much smaller saxagliptin studies20 suggested that (either as monotherapy or in combination) there was little impact on blood pressure with the DPP-4 inhibitor in comparison with placebo or metformin. The recent major DPP-4 inhibitor outcome studies have raised the hypothesis that heart failure may be precipitated and/or exacerbated with the use of these agents in the management of patients with diabetes. This is surprising given that preceding DPP-4 inhibitor data suggested potential for theoretical benefit with regard to HF, on the basis of the mechanisms outlined above.8, 9 This may represent play of chance and/or imbalances across study groups, but, if real, mechanisms urgently need to be elucidated. Until more data are available, guideline recommendations should be followed, but undoubtedly greater vigilance should be applied to recognizing the development of clinically significant HF in DPP-4 inhibitor-treated patients, including careful clinical assessment of heart failure symptoms and signs, together with (as required) ancillary objective assessments of heart failure status including measurement of plasma BNP levels and echocardiography. Two large-scale, placebo-controlled outcome trials, TECOS (with sitagliptin) and CARMELINA (with linagliptin), are due to report in the next few years, which should provide important data to support or refute the above hypothesis. In the meantime, a mechanistic explanation for this potential link should be further explored. Conflict of interest: none declared.

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists—which can be dosed to pharmacologic levels—act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%–1.7%) compared with DPP-4 inhibitors (0.4%–1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

Centaurea lycaonica is a local endemic species from the Centaurea L. genus. The Centaurea species has a wide range of usage in treating diseases in folk medicine. There are limited biological activity studies on this species in the literature. This study investigated enzyme inhibition and antimicrobial activity, antioxidant effect, and chemical content of extract and fractions of C. lycaonica. Enzyme inhibition activity was tested by α-amylase, α-glucosidase, and tyrosinase enzyme inhibition methods and antimicrobial activity by the microdilution method. The antioxidant activity was investigated using DPPH•, ABTS•+, and FRAP tests. The chemical content was determined by LC-MS/MS. The methanol extract showed the highest activity for α-glucosidase and α-amylase, even surpassing the positive control acarbose, with IC50 values of 56.333 ± 0.986 and 172.800 ± 0.816 μg/mL, respectively. Additionally, the ethyl acetate fraction also exhibited high activity for α-amylase with an IC50 value of 204.067 ± 1.739 μg/mL and tyrosinase with an IC50 value of 213.900 ± 1.553 μg/mL. Moreover, this extract and fraction were found to have the highest total phenolic and flavonoid contents and antioxidant activity. Additionally, LC-MS/MS analyses of active extract and fraction revealed mainly the presence of phenolic compounds and flavonoids. In silico molecular docking and molecular dynamics simulation studies of determining compounds apigenin and myristoleic acid, common in CLM and CLE extracts and active against α-glucosidase and α-amylase, were performed. In conclusion, methanol extract and ethyl acetate fraction showed potential enzyme inhibition and antioxidant activity as a natural agent. Molecular modeling studies corroborate the findings of in vitro activity analyses.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

In 1964, studies in just 2 subjects offered a simple, salient, and fundamental observation reported in 612 words: Glucose induces a greater insulin response when introduced through the gastrointestinal tract than when injected intravenously (the Figure, A).2 This finding built on studies dating to 1928 that injecting extracts of small intestine into animals lowered their glucose levels. Subsequently, this incretin effect was found to be mediated by glucagon-like peptide-1 (GLP1) and its action on pancreatic GLP1 receptors, in addition to contributions from glucose-dependent insulinotropic polypeptide.3,4 Moreover, the incretin response was found to be impaired in those with type 2 diabetes mellitus (T2D). We now know that the incretin axis also includes the enzyme dipeptidyl peptidase-IV (DPPIV), a serine protease that rapidly degrades GLP1 and other proteins.5 Ultimately, this arc of discovery led to new approved antidiabetic therapies: GLP1 analogs (exenatide, liraglutide) and DPPIV inhibitors (saxagliptin, sitagliptin, and, outside the United States, vildagliptin).4 For both classes of drugs, early preclinical experiments and smaller human studies suggest that targeting the incretin axis might address the elusive goal of an antidiabetic agent that improves cardiovascular disease.6,7 In the current issue of Circulation , Shah et al8 add this evolving story with their report that alogliptin, a DPPIV inhibitor in development, limits atherosclerosis and inflammation in 2 different mouse models. Given the increasing clinical use of approved incretin modulators, current large cardiovascular outcome trials with GLP1 agents and DPPIV inhibitors, and ongoing development of novel agents that target incretin signaling, further consideration of how the incretin axis might intersect the cardiovascular system is well warranted. Figure. A , The incretin effect. The well-documented phenomenon of oral glucose eliciting a higher insulin response than intravenous glucose at identical plasma levels of glucose is known as …

Background: Ganoderma fungus is rich in terpenoids. These compounds are known for their anti-hyperglycemic activities. However, the study of terpenoids as the secondary metabolite from Ganoderma as a dipeptidyl peptidase-4 (DPP-4) inhibitor remains unexplored. In addition, we examined the α-glucosidase inhibition activity. Objective: This study aimed to isolate the major terpenoid from non-laccate Ganoderma and examined its inhibitor activity on DPP-4 and α-glucosidase enzymes, and its interaction. Methods: The compound was isolated using column chromatography from Ganoderma australe. The structure of the isolated compound was confirmed by 1H and 13C nuclear magnetic resonance spectroscopy, while the inhibitory activity was evaluated using an enzymatic assay. The interaction of the isolated compound with DPP-4 and α-glucosidase enzymes was investigated using an in silico study. Results: The isolated compound was identified as stellasterol; IC50 values for DPP-4 and α-glucosidase inhibitor were 427.39 µM and 314.54 µM, respectively. This study revealed that the inhibitory effect of stellasterol on DPP-4 enzyme is through hydrophobic interaction, while the α-glucosidase enzyme is due to the interaction with six amino acids of the enzyme. Conclusion: Stellasterol is the major component of the steroid from G. australe. Enzyme inhibitory assay and in silico study suggest that stellasterol may contribute antidiabetic activity with a mechanism closer to acarbose rather than to sitagliptin.

Postprandial plasma glucose concentrations are an important contributor to glycemic control. There is evidence suggesting that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that predominantly reduce postprandial plasma glucose levels. DPP-4 inhibitors are associated with fewer gastrointestinal side effects than GLP-1 receptor agonists and are administered orally, unlike GLP-1 analogs, which are administered as subcutaneous injections. GLP-1 receptor agonists are somewhat more effective than DPP-4 inhibitors in reducing postprandial plasma glucose and are usually associated with significant weight loss. For these reasons, GLP-1 receptor agonists are generally preferred over DPP-4 inhibitors as part of combination treatment regimens in patients with glycated hemoglobin levels above 8.0%. This article reviews the pathogenesis of postprandial hyperglycemia, the mechanisms by which GLP-1 receptor agonists and DPP-4 inhibitors reduce postprandial plasma glucose concentrations, and the results of recent clinical trials (ie, published 2008 to October 2012) that evaluated the effects of these agents on postprandial plasma glucose levels when evaluated as monotherapy compared with placebo or as add-on therapy to metformin, a sulfonylurea, or insulin. Findings from recent clinical studies suggest that both GLP-1 receptor agonists and DPP-4 inhibitors could become valuable treatment options for optimizing glycemic control in patients unable to achieve glycated hemoglobin goals on basal insulin, with the added benefits of weight loss and a low risk of hypoglycemia.