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1.
J Diabetes Complications ; 36(7): 108225, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35690574

RESUMO

AIMS: Although the difference in HbA1c reduction between sodium-glucose cotransporter 2 (SGLT2) inhibitors and other oral glucose-lowering agents is relatively small, SGLT2 inhibitors exhibit beneficial cardiorenal protection. This study was based on the hypothesis that changes of HbA1c in patients treated with SGLT2 inhibitors may not accurately reflect an improved glycemic profile. METHODS: Two studies were conducted: 1) a retrospective cohort study of 3039 patients administered with either an SGLT2 or a dipeptidyl peptidase-4 (DPP4) inhibitor for 12 months comparing the changes in glycated albumin (GA) and HbA1c levels and 2) a pilot study of 10 patients whose glycemic dynamics were evaluated using flash glucose monitoring at baseline and 2 months after treatment with an SGLT2 inhibitor. RESULTS: SGLT2 inhibitors reduced GA more markedly than HbA1c in both studies. DPP4 inhibitors decreased both GA and HbA1c to a comparable degree. The mean glucose levels and glycemic standard deviation were significantly reduced after treatment with an SGLT2 inhibitor, in concordance with GA decline, although the lowering of HbA1c was marginal. CONCLUSIONS: Changes in HbA1c levels underestimated the glucose-lowering effect and the diminished glycemic fluctuation induced by SGLT2 inhibitors. Thus, the distinct biomarker roles of GA and HbA1c should be reevaluated.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hemoglobina A Glicada/análise , Produtos Finais de Glicação Avançada , Humanos , Hipoglicemiantes/uso terapêutico , Projetos Piloto , Estudos Retrospectivos , Albumina Sérica , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
2.
Nutrients ; 14(11)2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35684097

RESUMO

Time-restricted eating (TRE) has been shown to improve body weight and glucose metabolism in people at high risk of type 2 diabetes. However, the safety of TRE in the treatment of type 2 diabetes is unclear. We investigated the safety of TRE interventions in people with type 2 diabetes by identifying published and ongoing studies. Moreover, we identified the commonly used antidiabetic drugs and discussed the safety of TRE in people with type 2 diabetes considering the use of these drugs. In addition, we addressed the research needed before TRE can be recommended in the treatment of type 2 diabetes. A literature search was conducted to identify published (MEDLINE PubMed) and ongoing studies (ClinicalTrials.gov) on TRE in people with type 2 diabetes. To assess the usage of antidiabetic drugs and to discuss pharmacodynamics and pharmacokinetics in a TRE context, the most used antidiabetic drugs were identified and analysed. Statistics regarding sale of pharmaceuticals were obtained from MEDSTAT.DK which are based on data from the national Register of Medicinal Product Statistics, and from published studies on medication use in different countries. Four published studies investigating TRE in people with type 2 diabetes were identified as well as 14 ongoing studies. The completed studies suggested that TRE is safe among people with type 2 diabetes. Common antidiabetic drugs between 2010 and 2019 were metformin, insulin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sulfonylureas, and sodium-glucose cotransporter-2 inhibitors. Existing studies suggest that TRE is not associated with major safety issues in people with type 2 diabetes as long as medication is monitored and adjusted. However, because of low generalisability of the few studies available, more studies are needed to make concrete recommendations regarding efficacy and safety of TRE in people with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/uso terapêutico
3.
Food Res Int ; 156: 111176, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35651037

RESUMO

The objective of this study was to investigate the dipeptidyl peptidase IV (DPP-IV) inhibitory properties of quinoa protein-derived peptides. After germination, quinoa protein was extracted and then hydrolyzed by different enzymes such as papain, Alcalase, Neutrase, and Flavourzyme and pepsin-trypsin digestion. Results showed that the quinoa protein hydrolysates (QPH) by pepsin-trypsin digestion displayed the highest DPP-IV inhibitory activity. When ultrafiltrated, the fraction of quinoa protein hydrolysate with molecular weight less than 1 kDa (QPH1) exhibited a superior DPP-IV inhibitory activity with IC50 of 3.40 ± 0.20 mg/mL in vitro and 2.20 ± 0.29 mg/mL in Caco-2 based in situ. Furthermore, the peptide sequences of QPH1 were identified by UPLC-MS/MS. Twenty quinoa-derived peptides were determined with in vitro DPP-IV inhibitory activities with IC50 values less than 500 µM. The peptides IPI, IPV, VAYPL and IPIN showed the highest in vitro DPP-IV inhibitory activities with IC50 of 5.25 ± 0.16, 26.15 ± 0.58, 42.93 ± 1.15, and 56.58 ± 3.36 µM, respectively. The in situ DPP-IV activities of Caco-2 cells were also attenuated by these four peptides with IC50 of 10.75 ± 0.87, 29.11 ± 1.79, 61.9 ± 4.23, and 92.59 ± 12.89 µM, respectively. Moreover, these four peptides were identified as competitive inhibitors of DPP-IV. Molecular docking showed that quinoa peptides IPI and IPV were predicted to form multiple hydrogen bonds, attractive charge, and hydrophobic interactions with the residues of active site of DPP-IV. This study confirms that quinoa protein is a good source for DPP-IV inhibitory peptides and has potential as ingredients in functional foods for the prevention or management of type 2 diabetes.


Assuntos
Chenopodium quinoa , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Células CACO-2 , Chenopodium quinoa/metabolismo , Cromatografia Líquida , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Humanos , Simulação de Acoplamento Molecular , Pepsina A , Peptídeos/química , Hidrolisados de Proteína/química , Espectrometria de Massas em Tandem , Tripsina
4.
BMJ Open ; 12(6): e057977, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680274

RESUMO

INTRODUCTION: Therapeutic options for type 2 diabetes mellitus (T2DM) have expanded over the last decade with the emergence of cardioprotective novel agents, but without such data for older drugs, leaving a critical gap in our understanding of the relative effects of T2DM agents on cardiovascular risk. METHODS AND ANALYSIS: The large-scale evidence generations across a network of databases for T2DM (LEGEND-T2DM) initiative is a series of systematic, large-scale, multinational, real-world comparative cardiovascular effectiveness and safety studies of all four major second-line anti-hyperglycaemic agents, including sodium-glucose co-transporter-2 inhibitor, glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor and sulfonylureas. LEGEND-T2DM will leverage the Observational Health Data Sciences and Informatics (OHDSI) community that provides access to a global network of administrative claims and electronic health record data sources, representing 190 million patients in the USA and about 50 million internationally. LEGEND-T2DM will identify all adult, patients with T2DM who newly initiate a traditionally second-line T2DM agent. Using an active comparator, new-user cohort design, LEGEND-T2DM will execute all pairwise class-versus-class and drug-versus-drug comparisons in each data source, producing extensive study diagnostics that assess reliability and generalisability through cohort balance and equipoise to examine the relative risk of cardiovascular and safety outcomes. The primary cardiovascular outcomes include a composite of major adverse cardiovascular events and a series of safety outcomes. The study will pursue data-driven, large-scale propensity adjustment for measured confounding, a large set of negative control outcome experiments to address unmeasured and systematic bias. ETHICS AND DISSEMINATION: The study ensures data safety through a federated analytic approach and follows research best practices, including prespecification and full disclosure of results. LEGEND-T2DM is dedicated to open science and transparency and will publicly share all analytic code from reproducible cohort definitions through turn-key software, enabling other research groups to leverage our methods, data and results to verify and extend our findings.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/efeitos adversos , Reprodutibilidade dos Testes , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico
5.
Diab Vasc Dis Res ; 19(3): 14791641221106866, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35686694

RESUMO

While hemoglobin A1c (HbA1c) is commonly used to monitor therapy response in type 2 diabetes (T2D), GV is emerging as an essential additional metric for optimizing glycemic control. Our goal was to learn more about the impact of hypoglycemic agents on HbA1c levels and GV in patients with T2D. A systematic review and network meta-analysis (NMA) of randomized controlled trials were performed to assess the effects of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter (SGLT)-2 inhibitors, dipeptidyl peptidase (DPP)-4 inhibitors, sulfonylurea and thiazolidinediones on Mean Amplitude of Glycemic Excursions (MAGE) and HbA1c. Searches were performed using PubMed and EMBASE. A random-effect model was used in the NMA, and the surface under the cumulative ranking was used to rank comparisons. All studies were checked for quality according to their design and also for heterogeneity before inclusion in this NMA. The highest reduction in MAGE was achieved by GLP-1 RAs (SUCRA 0.83), followed by DPP-4 inhibitors (SUCRA: 0.72), and thiazolidinediones (SUCRA: 0.69). In terms of HbA1c reduction, GLP-1 RAs were the most effective (SUCRA 0.81), followed by DPP-4 inhibitors (SUCRA 0.72) and sulfonylurea (SUCRA 0.65). Our findings indicated that GLP-1 RAs have relatively high efficacy in terms of HbA1c and MAGE reduction when compared with other hypoglycemic agents and can thus have clinical application. Future studies with a larger sample size and appropriate subgroup analyses are warranted to completely understand the glycemic effects of these agents in various patients with T2D. The protocol for this systematic review was registered with the International Prospective Register of Systematic Reviews (CRD42021256363).


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Tiazolidinedionas , Glicemia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/efeitos adversos , Metanálise em Rede , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
7.
Molecules ; 27(12)2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35744987

RESUMO

Paramyosins, muscle proteins occurring exclusively in invertebrates, are abundant in seafoods. The potential of seafood paramyosins (SP) as sources of anti-angiotensin-converting-enzyme (ACE) and anti-dipeptidyl-peptidase (DPP-IV) peptides is underexplored. This in silico study investigated the release of anti-ACE and anti-DPP-IV peptides from SP after gastrointestinal (GI) digestion. We focused on SP of the common octopus, Humboldt squid, Japanese abalone, Japanese scallop, Mediterranean mussel, Pacific oyster, sea cucumber, and Whiteleg shrimp. SP protein sequences were digested on BIOPEP-UWM, followed by identification of known anti-ACE and anti-DPP-IV peptides liberated. Upon screening for high-GI-absorption, non-allergenicity, and non-toxicity, shortlisted peptides were analyzed via molecular docking and dynamic to elucidate mechanisms of interactions with ACE and DPP-IV. Potential novel anti-ACE and anti-DPP-IV peptides were predicted by SwissTargetPrediction. Physicochemical and pharmacokinetics of peptides were predicted with SwissADME. GI digestion liberated 2853 fragments from SP. This comprised 26 known anti-ACE and 53 anti-DPP-IV peptides exhibiting high-GI-absorption, non-allergenicity, and non-toxicity. SwissTargetPrediction predicted three putative anti-ACE (GIL, DL, AK) and one putative anti-DPP-IV (IAL) peptides. Molecular docking found most of the anti-ACE peptides may be non-competitive inhibitors, whereas all anti-DPP-IV peptides likely competitive inhibitors. Twenty-five nanoseconds molecular dynamics simulation suggests the stability of these screened peptides, including the three predicted anti-ACE and one predicted anti-DPP-IV peptides. Seven dipeptides resembling approved oral-bioavailable peptide drugs in physicochemical and pharmacokinetic properties were revealed: AY, CF, EF, TF, TY, VF, and VY. In conclusion, our study presented in silico evidence for SP being a promising source of bioavailable and safe anti-ACE and anti-DPP-IV peptides following GI digestions.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Tropomiosina , Inibidores da Enzima Conversora de Angiotensina/química , Quimioinformática , Digestão , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Dipeptidil Peptidases e Tripeptidil Peptidases , Simulação de Acoplamento Molecular , Peptídeos/química , Alimentos Marinhos
8.
Nutrients ; 14(12)2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35745109

RESUMO

Nowadays, notwithstanding their nutritional and technological properties, food bioactive peptides from plant sources garner increasing attention for their ability to impart more than one beneficial effect on human health. Legumes, which stand out thanks to their high protein content, represent valuable sources of bioactive peptides. In this context, this study focused on the characterization of the potential pleotropic activity of two commercially available soybean (SH) and pea (PH) protein hydrolysates, respectively. Since the biological activity of a specific protein hydrolysate is strictly correlated with its chemical composition, the first aim of the study was to identify the compositions of the SH and PH peptides. Peptidomic analysis revealed that most of the identified peptides within both mixtures belong to storage proteins. Interestingly, according to the BIOPEP-UWM database, all the peptides contain more than one active motive with known inhibitory angiotensin converting enzyme (ACE) and dipeptidyl-dipeptidases (DPP)-IV sequences. Indeed, the results indicated that both SH and PH inhibit DPP-IV and ACE activity with a dose-response trend and IC50 values equal to 1.15 ± 0.004 and 1.33 ± 0.004 mg/mL, and 0.33 ± 0.01 and 0.61 ± 0.05 mg/mL, respectively. In addition, both hydrolysates reduced the activity of DPP-IV and ACE enzymes which are expressed on the surface of human intestinal Caco-2 cells. These findings clearly support that notion that SH and PH may represent new ingredients with anti-diabetic and hypotensive effects for the development of innovative multifunctional foods and/or nutraceuticals for the prevention of metabolic syndrome.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Fabaceae , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células CACO-2 , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Humanos , Ervilhas/metabolismo , Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Soja/metabolismo
9.
Cardiovasc Diabetol ; 21(1): 118, 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35765074

RESUMO

BACKGROUND: Although a few meta-analyses were conducted to compare the risk of incident atrial fibrillation (AF) between sodium-glucose cotransporter-2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and other anti-hyperglycemic agents using indirect or direct comparison, the above analyses showed conflicting results with each other. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i, GLP-1RA, and dipeptidyl peptidase-4 inhibitor (DPP4i) among a large longitudinal cohort of diabetic patients. METHODS: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, a total of 344,893, 44,370, and 393,100 consecutive patients with type 2 diabetes without preexisting AF receiving GLP-1RA, SGLT2i, and DPP4i, respectively, were enrolled from May 1, 2016, to December 31, 2019. We used 1:1 propensity score matching (PSM) to balance covariates across paired study groups. Patients were followed from the drug index date until the occurrence of AF, death, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. RESULTS: After PSM, there were 245,442, 43,682, and 39,190 paired cohorts of SGLT2i-DPP4i, SGLT2i-GLP-1RA, and GLP-1RA-DPP4i, respectively. SGLT2i treatment was associated with lower risk of new-onset AF in participants with type 2 diabetes compared with either DPP4i [hazard ratio (HR):0.90; 95% confidential interval (CI) 0.84-0.96; P = 0.0028] or GLP-1RA [HR 0.74; 95% CI 0.63-0.88; P = 0.0007] treatment after PSM. There was no difference in the risk of incident AF between GLP-1RA and DPP4i users [HR 1.01; 95% CI 0.86-1.19; P = 0.8980]. The above findings persisted among several important subgroups. Dapagliflozin was specifically associated with a lower risk of new-onset AF compared with DPP4i (P interaction = 0.02). CONCLUSIONS: Compared with DPP4i, SGLT2i but not GLP-1RA was associated with a lower risk of incident AF in patients with type 2 diabetes.


Assuntos
Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/efeitos adversos , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
10.
BMJ ; 377: e068882, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35764326

RESUMO

OBJECTIVE: To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. DESIGN: Systematic review and pairwise and network meta-analysis. DATA SOURCES: PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021. ELIGIBILITY CRITERIA: Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs. MAIN OUTCOME MEASURES: Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. DATA EXTRACTION AND DATA SYNTHESIS: Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals. RESULTS: A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists. CONCLUSIONS: Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021271647.


Assuntos
Colecistite , Colelitíase , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Colelitíase/induzido quimicamente , Colelitíase/complicações , Colelitíase/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Glucose/uso terapêutico , Humanos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
11.
N Z Med J ; 135(1548): 77-88, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35728132

RESUMO

AIM: To determine what the variation was in the initial use of vildagliptin in patients with type 2 diabetes following approval of open access funding in October 2018, including by ethnicity, gender, age, funding model and patient HbA1c levels. METHODS: Data were collected from 31 general practices for all adult patients with type 2 diabetes. National Health Index-matched medication data were obtained from the national Pharmaceutical Collection. Patients were included for analysis if they had received at least one diabetes medication in the 12 months prior to funding approval for vildagliptin. The proportion of patients who initiated vildagliptin therapy following open access funding approval was then evaluated, as was the time taken until the first dispensing (days since funding approval). RESULTS: A total of 724 of 3,971 (18.2%) of patients initiated vildagliptin therapy; mean time to first dispensing was 192.1±112.4 days. In logistic regression, Asian patients were more likely and Maori less likely to receive vildagliptin than Europeans. Younger patients and those with an HbA1c of >64mmol/mol were also more likely to initiate therapy. Vildagliptin use by general practice ranged from 0.0-82.4%. CONCLUSIONS: Despite open access funding, there was inequity in the initial use of vildagliptin. Substantial variation by general practice indicates that practitioner education may be needed to ensure appropriate and early adoption of new diabetes medications.


Assuntos
Adamantano , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Acesso à Informação , Adamantano/uso terapêutico , Adulto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/efeitos adversos , Nova Zelândia , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Resultado do Tratamento , Vildagliptina/uso terapêutico
12.
Front Endocrinol (Lausanne) ; 13: 895458, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35692410

RESUMO

Aims: This study aimed to assess the impact of different antidiabetic agents on individuals with diabetes and COVID-19. Methods: We searched PubMed, Web of Science, Embase, and Cochrane Library databases from inception to October 31, 2021 and included seven antidiabetic agents. The data were pooled via traditional pairwise meta-analysis and Bayesian network meta-analysis. Results: The pairwise meta-analysis included 35 studies. Metformin (odds ratio (OR), 0.74; P=0.001), dipeptidyl peptidase-4 inhibitors (DPP4i) (OR, 0.88; P=0.04), sodium-glucose cotransporter-2 inhibitors (SGLT2i) (OR, 0.82; P=0.001), and glucagon-like peptide-1 receptor agonists (GLP1RA) (OR, 0.91; P=0.02) treatment were associated with lower COVID-19 mortality in individuals with diabetes compared to respective non-users. However, insulin treatment resulted in higher mortality (OR, 1.8; P=0.001). Mortality did not significantly differ in sulfonylurea (OR, 0.97; P=0.56) and thiazolidinediones (TZDs) (OR, 1.00; P=0.96) users. Furthermore, due to limited data, we analyzed five antidiabetic agents (metformin, DPP4i, sulfonylurea, insulin, and SGLT2i) and found no association between them and severe disease risk (all P>0.05). The Bayesian network meta-analysis included 18 studies. GLP1RA and SGLT2i had the highest first and second rank probability (67.3% and 62.5%, respectively). Insulin showed the maximum probability of ranking seventh (97.0%). Metformin had the third and fourth highest rank probability of 44.8% and 38.9%, respectively. Meanwhile, DPP4i had the fifth-highest rank probability of 42.4%, followed by sulfonylurea at 45.1%. Conclusion: Metformin, DPP4i, SGLT2i, and GLP1RA treatments were highly possible to reduced COVID-19 mortality risk in individuals with diabetes, while insulin might be related to increased mortality risk. Sulfonylurea and TZDs treatments were not associated with mortality. None of the antidiabetic agents studied were associated with the risk of severe disease. Additionally, GLP1RA probably had the most significant protective effect against death, followed by SGLT2i and metformin. Systematic Review Registration: PROSPERO (CRD42021288200).


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Tiazolidinedionas , Teorema de Bayes , COVID-19/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Metformina/uso terapêutico , Metanálise em Rede , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiazolidinedionas/uso terapêutico , Resultado do Tratamento
13.
Sci Rep ; 12(1): 10147, 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710921

RESUMO

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) potentially decrease all-cause and cardiovascular death, however, associations with non-cardiovascular death remain unclear. Therefore, we investigated SGLT2i associations with death and the cause of death. We used the Taiwanese National Health Institutes Research database linked to the National Register of Deaths (NRD). Incident type 2 diabetes mellitus (T2DM) patients and propensity score matched T2DM SGLT2i and Dipeptidyl peptidase 4 inhibitor (DPP4i) users were investigated. The index year was the SGLT2i or DPP4i prescription date from May 2016. Patients were followed-up until death or December 2018. Deaths verified by the NRD and grouped accordingly. Multiple Cox proportional hazards models were used. In total, 261,211 patients were included in the population; 47% of the patients were female and the average age was 62 years. The overall incidence of all-cause death was 8.67/1000 patient-years for SGLT2i and 12.41 for DPP4i users during follow-up. After adjusting for potential risk factors in the propensity score matched population, SGLT2i users were associated with lower risks of all-cause death, cardiovascular death, cancer death, and non-cancer, non-vascular death compared with DPP4i-users. For specific death causes, significantly lower death risks from heart disease, cerebrovascular disease, and accidents were associated with SGLT2i-use. SGLT2i benefits for T2DM patients were not different across subgroups. Compared with DPP4i-use, SGLT2i-use for T2DM was associated with lower disease and death risk.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Causas de Morte , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Incidência , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
14.
Front Endocrinol (Lausanne) ; 13: 900114, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35707460

RESUMO

Background: The prevalence of diabetes mellitus remains high in China, and more cardiovascular and cerebrovascular adverse events due to diabetes mellitus are likely to occur in the future. Objective: To analyze the gap between the current pharmacotherapy management and the guidelines for inpatients with type 2 diabetes mellitus from the perspective of pharmacists so as to provide a reference for optimal pharmacotherapy management methods and models for patients with type 2 diabetes mellitus. Methods: The study was a cross-sectional observational study. The study was conducted by investigating and analyzing the use of glucose-lowering drugs, adjustment of blood pressure management strategy, lipid management, weight management, and application of antiplatelet drugs in type 2 diabetes inpatients. Results: A total of 1086 patients with type 2 diabetes were included. Metformin, glycosidase inhibitors, and basal insulin were the most used among type 2 diabetes inpatients. The use of SGLT-2, GLP-1 RAs, DPP-4, and metformin all showed significant increase. SGLT-2 inhibitors (SGLT-2i) showed the fastest increase from 2020 to 2021 (14.5% vs. 39.6%); However, the application rate of SGLT-2i was low among patients with combined ASCVD, renal insufficiency, and diabetic nephropathy (46.4%, 40.9%, and 45.8% respectively). For patients with substandard blood pressure at admission, the average rate of intervention by endocrinologists for adjusting the antihypertensive regimen during hospitalization was 55.6%, and the application rate of ACEI/ARB drugs reached 64.4%. The application rate of statins among patients with type 2 diabetes was still relatively high, at 78.8%. However, the overall intervention rate for patients with suboptimal LDL-c was only 24.1%. The application rate of antiplatelet agents for patients with ASCVD was 77.6%, which was higher than that for patients without ASCVD. Conclusion: There is still a gap between the practice of medication treatment management of Chinese inpatients with type 2 diabetes and the guidelines, especially in the application of GLP-1RAs and SGLT-2i in patients with concomitant ASCVD, diabetic nephropathy, and renal insufficiency. Meanwhile, physicians and pharmacists should pay more attention on achieving blood pressure and LDL-c standards in type 2 diabetic patients and provide timely interventions.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Inibidores da Dipeptidil Peptidase IV , Metformina , Insuficiência Renal , Inibidores do Transportador 2 de Sódio-Glicose , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , LDL-Colesterol , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Pacientes Internados , Metformina/uso terapêutico , Farmacêuticos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
15.
Front Endocrinol (Lausanne) ; 13: 893971, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721733

RESUMO

Our study aimed to evaluate the exposure-response relationship between incretin-based medications and the risk of major adverse cardiovascular events (MACE) using cardiovascular outcome trials (CVOTs). Eleven CVOTs with incretin-based medications were included. The median follow-up time, percentage of time exposure, and hazard ratio (HR) of MACE were obtained from each CVOT. The pharmacokinetic parameters of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitor (DPP-4) were obtained from published studies. Regression analysis was performed to assess the relationship between drug exposure and MACE HR. Cutoff values were determined from the ROC curves. The linear regression results indicated that log Cmax, log AUC0-24h, and log AUCCVOT are negatively correlated with MACE HR (R2 = 0.8494, R2 = 0.8728, and R2 = 0.8372, respectively; all p < 0.0001). The relationship between drug exposure (log Cmax, log AUC0-24h, and log AUCCVOT) and MACE HR strongly corresponded with the log (inhibitor) vs. response curve (R2 = 0.8383, R2 = 0.8430, and R2 = 0.8229, respectively). The cutoff values in the ROC curves for log Cmax, log AUC0-24h, and log AUCCVOT, were 2.556, 3.868, and 6.947, respectively (all p = 0.007). A Fisher's exact test revealed that these cutoff values were significantly related to cardiovascular benefits (all p < 0.05). Our study revealed a linear exposure-response relationship between drug exposure and MACE HR. We conclude that the cardiovascular benefits of incretin-based therapies may occur with higher doses of GLP-1 RAs and with increased exposure.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Incretinas/uso terapêutico
16.
Clin J Am Soc Nephrol ; 17(6): 835-842, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35618342

RESUMO

BACKGROUND AND OBJECTIVES: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been associated with a higher risk of skeletal fractures in some randomized, placebo-controlled trials. Secondary hyperparathyroidism and increased bone turnover (also common in CKD) may contribute to the observed fracture risk. We aimed to determine if SGLT2 inhibitor use associates with a higher risk of fractures compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which have no known association with fracture risk. We hypothesized that this risk, if present, would be greatest in patients with lower eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a population-based cohort study in Ontario, Canada between 2015 and 2019 using linked provincial administrative data to compare the incidence of fracture between new users of SGLT2 inhibitors and DPP-4 inhibitors. We used inverse probability of treatment weighting on the basis of propensity scores to balance the two groups of older adults (≥66 years of age) on indicators of baseline health. We compared the 180- and 365-day cumulative incidence rates of fracture between groups. Prespecified subgroup analyses were conducted by eGFR category (≥90, 60 to <90, 45 to <60, and 30 to <45 ml/min per 1.73 m2). Weighted hazard ratios were obtained using Cox proportional hazard regression. RESULTS: After weighting, we identified a total of 38,994 new users of a SGLT2 inhibitor and 37,449 new users of a DPP-4 inhibitor and observed a total of 342 fractures at 180 days and 689 fractures at 365 days. The weighted 180- and 365-day risks of a fragility fracture did not significantly differ between new users of a SGLT2 inhibitor versus a DPP-4 inhibitor: weighted hazard ratio, 0.95 (95% confidence interval, 0.79 to 1.13) and weighted hazard ratio, 0.88 (95% confidence interval, 0.88 to 1.00), respectively. There was no observed interaction between fracture risk and eGFR category (P=0.53). CONCLUSIONS: In this cohort study of older adults, starting a SGLT2 inhibitor versus DPP-4 inhibitor was not associated with a higher risk of skeletal fracture, regardless of eGFR.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Fraturas Ósseas , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Fraturas Ósseas/induzido quimicamente , Fraturas Ósseas/epidemiologia , Glucose , Humanos , Hipoglicemiantes , Ontário , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
17.
World J Gastroenterol ; 28(17): 1814-1829, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35633911

RESUMO

BACKGROUND: Obesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation. AIM: To address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice. METHODS: Male C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin). RESULTS: The HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation. CONCLUSION: PPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Endotoxemia , Hepatopatia Gordurosa não Alcoólica , Obesidade , PPAR alfa , Animais , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Disbiose/tratamento farmacológico , Disbiose/metabolismo , Endotoxemia/complicações , Endotoxemia/tratamento farmacológico , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Filogenia
18.
Inflamm Res ; 71(5-6): 711-722, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35578028

RESUMO

OBJECTIVE: Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, in our previous short-term (35 days) studies, we showed that sitagliptin accentuates the hepato-inflammatory effects of high dietary cholesterol (Cho) in male Sprague-Dawley rats. Since most type 2 diabetics also present with lipid abnormalities and use DPP-4 inhibitors for glucose management, the present study was conducted to assess the impact of sitagliptin during long-term (98 days) feeding of a high Cho diet. An additional component of the present investigation was the inclusion of other gliptins to determine if hepatic steatosis, necro-inflammation, and fibrosis were specific to sitagliptin or are class effects. METHODS: Adult male Sprague-Dawley rats were fed control or high Cho (2.0%) diets, and gavaged daily (from day 30 through 98) with vehicle or DPP-4 inhibitors (sitagliptin or alogliptin or saxagliptin). On day 99 after a 4 h fast, rats were euthanized. Blood and liver samples were collected to measure lipids and cytokines, and for histopathological evaluation, determination of hepatic lesions (steatosis, necrosis, inflammation, and fibrosis) using specific staining and immunohistochemical methods. RESULTS: Compared to controls, the high Cho diet produced a robust increase in NASH like phenotype that included increased expression of hepatic (Tnfa, Il1b, and Mcp1) and circulatory (TNFα and IL-1ß) markers of inflammation, steatosis, necrosis, fibrosis, and mononuclear cell infiltration. These mononuclear cells were identified as macrophages and T cells, and their recruitment in the liver was facilitated by marked increases in endothelium-expressed cell adhesion molecules. Importantly, treatment with DPP-4 inhibitors (3 tested) neither alleviated the pathologic responses induced by high Cho diet nor improved lipid profile. CONCLUSIONS: The potential lipid lowering effects of DPP-4 inhibitors were diminished by high Cho (a significant risk factor for inducing liver damage). The robust inflammatory responses induced by high Cho feeding in long-term experiment were not exacerbated by DPP-4 inhibitors and a consistent hepatic inflammatory environment persisted, implying a prospective physiological adaptation.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Hipercolesterolemia , Animais , Colesterol na Dieta , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Fibrose , Hipoglicemiantes , Inflamação/patologia , Masculino , Necrose/tratamento farmacológico , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Fosfato de Sitagliptina/farmacologia , Fosfato de Sitagliptina/uso terapêutico
20.
BMJ Open ; 12(5): e056885, 2022 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-35584872

RESUMO

INTRODUCTION: Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%-9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters. ETHICS AND DISSEMINATION: This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020-013). TRIAL REGISTRATION NUMBER: UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Peptídeos Semelhantes ao Glucagon , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
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