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1.
Value Health ; 23(2): 217-226, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32113627

RESUMO

OBJECTIVES: Inappropriate use of the case-crossover design, which is efficient for examining associations between brief exposure and abrupt outcomes, in evaluating the effects of medications in the presence of exposure-time trends or persistent drug use may generate spurious associations. We compared different approaches to adjusting for these sources of bias by examining the risk of heart failure hospitalization (HFH) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors. Overall, existing evidence does not suggest a higher risk of HFH associated with DPP-4 inhibitors; however, case-crossover analyses of these medications may be susceptible to bias. METHODS: We conducted case-crossover; age, sex, risk-set (ASR) matched case-time-control; disease risk score (DRS)-matched case-time-control; and case-case-time-control analyses to assess the association between DPP-4 inhibitors and HFH among patients with diabetes mellitus (DM) in a population-based Taiwanese database. We also examined metformin and sulfonylureas, both with assumed null associations. RESULTS: Among 362 022 DM patients, 4105 (case-crossover), 4103 (ASR-matched case-time-control), 3957 (DRS-matched case-time-control), and 2812 (case-case-time-control) HFH cases were identified. The OR for DPP-4 inhibitors and HFH was elevated in the case-crossover analysis (1.52; 95% confidence interval [95% CI] 0.95-2.42). The ASR-matched case-time control, DRS-matched case-time-control, and case-case-time control analyses yielded near-null associations (0.90 [95% CI 0.45-1.83], 0.96 [95% CI 0.46-2.02], and 0.92 [95% CI 0.39-2.21], respectively). Null effects were observed for metformin across designs and for sulfonylureas in the case-case-time control analysis. CONCLUSIONS: Our case-crossover analysis suggested DPP-4 inhibitors may be associated with HFH; however, each method for adjusting for exposure-time and persistent user bias attenuated the findings. The case-case-time-control analysis had the least precision.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Cardíaca/terapia , Hospitalização , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Viés , Estudos de Casos e Controles , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Incidência , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Farmacoepidemiologia , Medição de Risco , Fatores de Risco , Compostos de Sulfonilureia/efeitos adversos , Taiwan/epidemiologia , Fatores de Tempo , Resultado do Tratamento
2.
Mayo Clin Proc ; 95(1): 101-112, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812252

RESUMO

OBJECTIVES: To estimate inappropriate dosing of dipeptidyl peptidase-4 (DPP-4) inhibitors and to assess the risk of emergency department visits, hypoglycemia, and mortality in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) prescribed inappropriate DPP-4 inhibitor doses because limited real-world information is available regarding rates of DPP-4 inhibitor dose adjustment and its safety in patients with T2DM and CKD. PATIENTS AND METHODS: We performed a retrospective observational cohort study of 82,332 patients aged 30 to 75 years with T2DM and CKD being treated with DPP-4 inhibitors from January 1, 2012, through December 31, 2014, using the Korean National Health Information Database. We divided the patients according to the prescription of DPP-4 inhibitor with or without dose adjustment according to estimated glomerular filtration rate. The incidences of emergency department visits, hypoglycemia, and mortality were assessed using hazard ratios estimated using Cox proportional hazards regression modeling. RESULTS: Approximately 40% of patients with T2DM and CKD were prescribed an inappropriate dose of DPP-4 inhibitor from 2009 through 2011; this proportion decreased to 24.4% in 2015. Hazard ratios (95% CIs) for inappropriate vs appropriate dosing of DPP-4 inhibitors were 1.115 (1.005-1.237) for mortality, 1.074 (1.018-1.133) for emergency department visits, and 1.192 (1.054-1.349) for severe hypoglycemia after multivariable adjustment for confounding factors. CONCLUSION: One of every 3 patients with T2DM and CKD received inappropriate dosing of DPP-4 inhibitor, which was associated with high risk of emergency department visits, severe hypoglycemia, and mortality.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hipoglicemia , Prescrição Inadequada , Insuficiência Renal Crônica , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Prescrição Inadequada/efeitos adversos , Prescrição Inadequada/estatística & dados numéricos , Testes de Função Renal/métodos , Masculino , Pessoa de Meia-Idade , Mortalidade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , República da Coreia/epidemiologia , Estudos Retrospectivos , Medição de Risco
3.
J Manag Care Spec Pharm ; 26(1): 67-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31880221

RESUMO

BACKGROUND: Adherence and persistence with diabetes medication play an important role in glycemic control and may differ by medication class. However, there is a lack of research comparing diabetes medications in patients with renal impairment, despite the challenges and higher burden associated with managing this population. OBJECTIVE: To compare adherence and persistence among patients with type 2 diabetes mellitus (T2DM) and nondialysis chronic kidney disease (CKD) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors versus pioglitazone. METHODS: This retrospective cohort study used Truven MarketScan administrative claims databases from 2009 to 2015. One-year adherence for patients with T2DM and nondialysis CKD who initiated therapy with either a DPP-4 inhibitor or pioglitazone was measured by proportion of days covered (PDC) following an initial dispensing, and PDC ≥ 0.80 was coded as adherent. Persistence was calculated as the days between the index date and last day with the index medication on hand, based on the end of the last days supply or the end of follow-up (i.e., 365 days), whichever occurred first. Multivariate logistic regression and Cox proportional hazards models were used to estimate confounder-adjusted differences between the groups for adherence and persistence. RESULTS: The final cohort included 9,019 patients (DPP-4 inhibitors: 7,002; pioglitazone: 2,017). In the adjusted analysis, DPP-4 inhibitor users demonstrated a 1.41 (95% CI = 1.25-1.59) higher odds of being adherent compared with pioglitazone users. Overall adjusted HR for persistence was 0.74 (95% CI = 0.69-0.79), which favored DPP-4 inhibitors compared with pioglitazone. Relative to 2010, persistence with pioglitazone decreased in 2011-2012 and then increased in 2013-2014. In the subgroup analysis, DPP-4 inhibitors first had lower (2010: OR = 0.78, 95% CI = 0.70-0.87; 2011-2012: OR = 0.60, 95% CI = 0.54-0.66) and then similar (2013-2014: OR = 1.03, 95% CI = 0.88-1.19) hazards of nonpersistence compared with pioglitazone. CONCLUSIONS: Among patients with T2DM and nondialysis CKD, the use of DPP-4 inhibitors was associated with better adherence compared with pioglitazone. However, following the approval of generic pioglitazone and associated lower cost sharing after 2012, the magnitude of difference in adherence between the medication classes reduced. Similarly, safety warnings in 2011 and approval of generic products in 2012 may have affected pioglitazone persistence, leading to first higher and then similar hazards for nonpersistence with pioglitazone as compared with DPP-4 inhibitors. These shifts in the results for pioglitazone warrant further investigation and close monitoring of the population initiating this medication. DISCLOSURES: No funding was received for this study. The authors have no conflicts of interest to disclose. An abstract for this study was presented as a podium presentation at the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) 2019 Annual Meeting; May 18-22, 2019; New Orleans, LA.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Medicamentos Genéricos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Adesão à Medicação , Pioglitazona/uso terapêutico , Padrões de Prática Médica , Insuficiência Renal Crônica/tratamento farmacológico , Demandas Administrativas em Assistência à Saúde , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Progressão da Doença , Substituição de Medicamentos , Uso de Medicamentos , Medicamentos Genéricos/efeitos adversos , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Seguro de Serviços Farmacêuticos , Masculino , Pessoa de Meia-Idade , Pioglitazona/efeitos adversos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
4.
BMC Cardiovasc Disord ; 19(1): 311, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870322

RESUMO

BACKGROUND: The most significant manifestation of heart failure is exercise intolerance. This systematic review and meta-analysis was performed to investigate whether dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1 RAs), widely used anti-diabetic drugs, could improve exercise tolerance in heart failure patients with or without type 2 diabetes mellitus. METHODS: An electronic search of PubMed, EMBASE and the Cochrane Library was carried out through March 8th, 2019, for eligible trials. Only randomized controlled studies were included. The primary outcome was exercise tolerance [6-min walk test (6MWT) and peak O2 consumption], and the secondary outcomes included quality of life (QoL), adverse events (AEs) and all-cause death. RESULT: After the literature was screened by two reviewers independently, four trials (659 patients) conducted with heart failure patients with or without type 2 diabetes met the eligibility criteria. The results suggested that targeting the DPP-4-GLP-1 pathway can improve exercise tolerance in heart failure patients [MD 24.88 (95% CI 5.45, 44.31), P = 0.01] without decreasing QoL [SMD -0.51 (95% CI -1.13, 0.10), P = 0.10]; additionally, targeting the DPP-4-GLP-1 pathway did not show signs of increasing the incidence of serious AEs or mortality. CONCLUSION: Our results suggest that DPP-4 inhibitors or GLP-1 RAs improve exercise tolerance in heart failure patients. Although the use of these drugs for heart failure has not been approved by any organization, they may be a better choice for type 2 diabetes mellitus patients with heart failure. Furthermore, as this pathway contributes to the improvement of exercise tolerance, it may be worth further investigation in exercise-intolerant patients with other diseases.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Insuficiência Cardíaca/tratamento farmacológico , Incretinas/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Incretinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Transdução de Sinais , Resultado do Tratamento
6.
Cardiovasc Diabetol ; 18(1): 158, 2019 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-31733647

RESUMO

BACKGROUND: Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain. AIM AND METHODS: We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353). RESULTS: There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 µg/mL vs. 52 weeks, 1.4 ± 1.0 µg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 µg/mL vs. 52 weeks, 1.3 ± 0.7 µg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06). CONCLUSION: These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.


Assuntos
LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirimidinas/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Idoso , Biomarcadores/sangue , Colesterol/análogos & derivados , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Japão , Masculino , Pessoa de Meia-Idade , Fitosteróis/sangue , Pirimidinas/efeitos adversos , Fosfato de Sitagliptina/efeitos adversos , Sitosteroides/sangue , Fatores de Tempo , Resultado do Tratamento
8.
BMJ Case Rep ; 12(9)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570343

RESUMO

Dipeptidyl peptidase 4 (DPP-4) inhibitors are increasingly used these days in management of diabetes. There has been reported in a few case reports of increasing association between DPP-4 inhibitor use and bullous pemphigoid (BP). We report a case of association between linagliptin use and BP and subsequent treatment with rituximab.


Assuntos
Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Erupção por Droga/patologia , Linagliptina/efeitos adversos , Penfigoide Bolhoso/induzido quimicamente , Rituximab/uso terapêutico , Idoso , Antibacterianos/uso terapêutico , Clobetasol/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Erupção por Droga/tratamento farmacológico , Humanos , Linagliptina/administração & dosagem , Masculino , Minociclina/uso terapêutico , Penfigoide Bolhoso/patologia , Prednisona/uso terapêutico , Resultado do Tratamento
9.
Expert Opin Drug Saf ; 18(11): 1099-1108, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31519110

RESUMO

Objectives: To examine the signals of bullous pemphigoid (BP) with dipeptidyl peptidase-4 inhibitors (DPP-4i) in VigiBase® and the potential role of their pharmacodynamic/pharmacokinetic parameters in the occurrence of BP. Methods: Case/non-case analyses were performed in VigiBase® to examine the signal of BP [reporting odds ratio (ROR)] for gliptins. Secondly, the authors performed linear regression analyses to explore the association between DPP-4i signals for BP and their affinities toward different target enzymes (DPP-2, DPP-4, DPP-8, and DPP-9) and their volume of distribution (Vd). Results: A significant BP signal was found for DPP-4i. The ROR for pooled DPP-4i was 179.48 (95% CI: 166.41-193.58). The highest ROR was found for teneligliptin 975.04 (801.70-1185.87) and lowest for saxagliptin 18.9 (11.5-30.9). Linear regression analyses showed a considerable trend to significance for the linear correlation between the BP signal and gliptin affinity at DPP-4 (slope = 1.316 [-0.4385-3.21], p = 0.067, R2 = 0.40) but not the other enzyme targets, nor for Vd. Conclusion: The findings suggest a clinical relevance of gliptins selectivity for DDP-4 in the development of BP as a result of exposure to these drugs. Future preclinical and clinical studies are needed for a better understanding of this correlation.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Penfigoide Bolhoso/induzido quimicamente , Farmacovigilância , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais/estatística & dados numéricos , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/epidemiologia , Distribuição Tecidual
10.
J Korean Med Sci ; 34(35): e224, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31496139

RESUMO

BACKGROUND: There have been equivocal results in studies of the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i) on fractures. In this study, we analyzed the effect of DPP-4i on bone fracture risk in a Korean population. METHODS: We extracted subjects (n = 11,164) aged 50 years or older from the National Health Insurance Service-National Sample Cohort 2.0 from 2009 to 2014. Our control group included subjects without diabetes (n = 5,582), and our treatment groups with diabetes included DPP-4i users (n = 1,410) and DPP-4i non-users (n = 4,172). The primary endpoint was the incidence of a composite outcome consisting of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures. The secondary endpoint was the incidence of each individual component of the composite outcome. Survival analysis was performed with adjustment for age, gender, diabetes complications severity index, Charlson comorbidity index, hypertension medication, and dyslipidemia treatment. RESULTS: The incidence of the composite outcome per 1,000 person-years was 0.089 in DPP-4i users, 0.099 in DPP-4i non-users, and 0.095 in controls. There was no significant difference in fracture risk between DPP-4i users and DPP-4i non-users or controls after the adjustments (P > 0.05). The incidences of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures were not significantly different between DPP-4i users and non-users. The results of subgroup analyses by gender and age were consistent. CONCLUSION: DPP-4i had no significant effect on the risk of fractures in a Korean population.


Assuntos
Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Fraturas Ósseas/diagnóstico , Hipoglicemiantes/efeitos adversos , Idoso , Estudos de Coortes , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Humanos , Hipoglicemiantes/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Osteoporose/etiologia , República da Coreia/epidemiologia , Fatores de Risco
11.
Cardiovasc Diabetol ; 18(1): 116, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481069

RESUMO

BACKGROUND: To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). METHODS: TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses. RESULTS: During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81-1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83-1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83-1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes. CONCLUSIONS: In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Cardíaca/terapia , Hospitalização , Infarto do Miocárdio/terapia , Fosfato de Sitagliptina/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etnologia , Insuficiência Cardíaca/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/mortalidade , Medição de Risco , Fatores de Risco , Fosfato de Sitagliptina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
12.
BMJ Case Rep ; 12(8)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31444259

RESUMO

Sitagliptin is a dipeptidyl peptidase-4 inhibitor commonly used in the treatment of type 2 diabetes mellitus for glycaemic control. Concerns have arisen regarding adverse events caused by this drug, particularly concerning arthralgias. Here, we report on a 56-year-old man being treated with sitagliptin who developed inflammatory arthritis after taking the drug for 6 months. The patient presented with pain, swelling and erythema in multiple joints and was eventually diagnosed with seronegative rheumatoid arthritis (RA) under the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria. His symptoms continued for several months after stopping sitagliptin and eventually went into remission after a tapered course of steroids, hydroxychloroquine and methotrexate. Furthermore, the patient is HLA-DRB3 positive, a genetic marker that is still being investigated for its role in the pathogenesis of RA and that may have been a predisposing factor in the development of this patient's inflammatory arthropathy.


Assuntos
Artrite Reumatoide/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/efeitos adversos , Fosfato de Sitagliptina/efeitos adversos , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/genética , Diagnóstico Diferencial , Cadeias HLA-DRB3/genética , Humanos , Masculino , Pessoa de Meia-Idade
13.
BMJ ; 366: l4772, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467044

RESUMO

OBJECTIVE: To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. DESIGN: Cohort study using data from nationwide registers and an active-comparator new-user design. SETTING: Denmark, Norway, and Sweden, from April 2013 to December 2016. PARTICIPANTS: 20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score. MAIN OUTCOME MEASURES: Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios. RESULTS: Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death. CONCLUSIONS: In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.


Assuntos
Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Insuficiência Cardíaca/epidemiologia , Infarto do Miocárdio/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Idoso , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Seguimentos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/induzido quimicamente , Noruega/epidemiologia , Sistema de Registros/estatística & dados numéricos , Acidente Vascular Cerebral/induzido quimicamente , Suécia/epidemiologia
14.
Cardiovasc Drugs Ther ; 33(5): 547-555, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31418140

RESUMO

PURPOSE: A multicentre, randomized, double-blind, placebo-controlled, parallel-group study aimed to define the potential positive effect of dipeptidyl peptidase-4 inhibition on left ventricular systolic function (LVSF) beyond glycemic control in type 2 diabetes mellitus (T2DM) (DYDA 2™ trial). METHODS: Individuals with fairly controlled T2DM and asymptomatic impaired LVSF were randomized in a 1:1 ratio to receive for 48 weeks either linagliptin 5 mg daily or placebo, in addition to their stable diabetes therapy. Eligibility criteria were age ≥ 40 years, history of T2DM with a duration of at least 6 months, HbA1c ≤ 8.0% (≤ 64 mmol/mol), no history or clinical signs/symptoms of cardiac disease, evidence at baseline echocardiography of concentric LV geometry (relative wall thickness ≥ 0.42), and impaired LVSF defined as midwall fractional shortening (MFS) ≤ 15%. The primary end-point was the modification from baseline to 48 weeks of MFS. As an exploratory analysis, significant changes in LV global longitudinal strain and global circumferential strain, measured by speckle tracking echocardiography, were also considered. Secondary objectives were changes in diastolic and/or in systolic longitudinal function as measured by tissue Doppler. RESULTS: A total of 188 patients were enrolled. They were predominantly males, mildly obese, with typical insulin-resistance co-morbidities such as hypertension and dyslipidemia. Mean relative wall thickness was 0.51 ± 0.09 and mean MFS 13.3% ± 2.5. CONCLUSIONS: DYDA 2 is the first randomized, double-blind, placebo-controlled trial to explore the effect of a dipeptidyl peptidase-4 inhibitor on LVSF in T2DM patients in primary prevention regardless of glycemic control. The main characteristics of the enrolled population are reported. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT02851745.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Linagliptina/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Adulto , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Itália , Linagliptina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia
15.
Cardiovasc Diabetol ; 18(1): 112, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462224

RESUMO

BACKGROUND: Recent trials suggested that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduced cardiovascular events. Comparative effectiveness of these new antidiabetic drug classes remains unclear. We therefore performed a network meta-analysis to compare the effect on cardiovascular outcomes among GLP-1 RAs, SGLT-2 and dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: MEDLINE, EMBASE, Cochrane database, ClinicalTrials.gov, and congress proceedings from recent cardiology conferences were searched up to April 20, 2019. Cardiovascular outcome trials and renal outcome trials reporting cardiovascular outcomes on GLP-1 RAs, SGLT-2 and DPP-4 inhibitors in patients with type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality, all-cause mortality, hospitalisation for heart failure (HF), and renal composite outcome. ORs and 95% CI were calculated using random-effects models. RESULTS: Fourteen trials enrolling 121,047 patients were included. SGLT-2 inhibitors reduced cardiovascular deaths and all-cause deaths compared to placebo (OR 0.82, 95% CI 0.73-0.93 and OR 0.84, 95% CI 0.77-0.92) and DPP-4 inhibitors (OR 0.83, 95% CI 0.70-0.99 and OR 0.83, 95% CI 0.73-0.94), respectively. SGLT-2 inhibitors and GLP-1 RAs significantly reduced MACE (OR 0.88, 95% CI 0.82-0.95 and OR 0.87, 95% CI 0.82-0.93), hospitalisation for HF (OR 0.68, 95% CI 0.61-0.77 and OR 0.87, 95% CI 0.82-0.93), and renal composite outcome (OR 0.59, 95% CI 0.52-0.67 and OR 0.86, 95% CI 0.78-0.94) compared to placebo, but SGLT-2 inhibitors reduced hospitalisation for HF (OR 0.79, 95% CI 0.69-0.90) and renal composite outcome (OR 0.69, 95% CI 0.59-0.80) more than GLP-1 RAs. Only GLP-1 RAs reduced nonfatal stroke (OR 0.88, 95% CI 0.77-0.99). DPP-4 inhibitors did not lower the risk of these outcomes when compared to placebo and were associated with higher risks of MACE, hospitalisation for HF, and renal composite outcome when compared to the other two drug classes. CONCLUSIONS: SGLT-2 inhibitors show clear superiority in reducing cardiovascular and all-cause deaths, hospitalisation for HF, and renal events among new antidiabetic drug classes. GLP-1 RAs also have cardiovascular and renal protective effects. DPP-4 inhibitors have no beneficial cardiovascular effects and are therefore inferior to the other two drug classes. SGLT-2 inhibitors should now be the preferred treatment for type 2 diabetes mellitus.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Incretinas/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Causas de Morte , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hospitalização , Humanos , Incretinas/efeitos adversos , Metanálise em Rede , Medição de Risco , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
Immunol Med ; 42(1): 22-28, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31169082

RESUMO

Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated autoimmune blistering skin disorder that tends to affect the elderly. Tense blister formation associated with itchy urticarial erythema is clinically observed in BP, and subepidermal blister formation with eosinophilic infiltration is a histopathological characteristic. BP autoantibodies target two hemidesmosomal components in basal keratinocytes: BP180 and BP230. Anti-BP180 autoantibodies play major roles in blister formation. Although the autoantibody-mediated pathomechanism of blister formation has been extensively studied, little is known about how and why immune tolerance to BP180 may be broken in certain elderly individuals. Recently, BP has been increasingly reported in diabetes mellites (DM) patients receiving dipeptidyl peptidase-IV inhibitors (DPP4is), which are widely used anti-DM drugs. Pharmacovigilance and cohort studies have revealed that DPP4is, especially vildagliptin, teneligliptin, and linagliptin, are a potential risk factor for BP onset. Interestingly, it has been revealed that Japanese DPP4i-BP tends to show a non-inflammatory phenotype, with less erythema than normal BP, and that DPP4i-BP autoantibodies target distinct epitopes on BP180. In addition, human leukocyte antigen-DQB1*03:01 was identified as the major haplotype in Japanese DPP4i-BP. This review summarizes the latest understanding of the pathogenesis of BP, with a special focus on the recently recognized DPP4i-BP.


Assuntos
Autoimunidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/administração & dosagem , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/imunologia , Grupo com Ancestrais do Continente Asiático , Autoanticorpos , Autoantígenos/imunologia , Epitopos , Cadeias beta de HLA-DQ/genética , Haplótipos , Humanos , Tolerância Imunológica/imunologia , Linagliptina/efeitos adversos , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/genética , Pirazóis/efeitos adversos , Fatores de Risco , Tiazolidinas/efeitos adversos , Vildagliptina/efeitos adversos
17.
Expert Opin Drug Saf ; 18(8): 691-701, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31150300

RESUMO

INTRODUCTION: Oral antidiabetic medications are important in many type 2 diabetes care plans. AREAS COVERED: The article summarizes the cardiovascular and renal safety data for DPP-4 inhibitors and SGLT-2 inhibitors and specific safety data particular to each class. EXPERT OPINION: DPP-4 and SGLT-2 inhibitors provide unique anti-hyperglycemic mechanisms. The cardiovascular safety profiles of DPP-4 inhibitors are promising, but do not show the strong CV risk reduction of empagliflozin and canagliflozin. The heart failure signal associated with DPP-4 inhibitor use is unclear with differing agents, demonstrating increased risk or maybe even protective effects. The risk reduction in cardiovascular disease associated with SGLT-2 inhibitors has translated to recommendations to consider these therapies early in the treatment pathway. Both classes have potential safety concerns that necessitate appropriate patient selection and thorough education on potential side-effects. DPP-4 inhibitors are considered to have neutral or in some studies beneficial renoprotective effects. SGLT-2 inhibitor safety effects on the kidney are more complex. There are reports of acute kidney injury occurring soon after initiating SGLT-2 inhibitor therapy. However, there are large recent studies that have demonstrated the beneficial effect of SGLT-2 inhibitors in slowing the progression of established chronic kidney disease.


Assuntos
Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Administração Oral , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Canagliflozina/administração & dosagem , Canagliflozina/efeitos adversos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Seleção de Pacientes , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
18.
Diabetes Care ; 42(8): 1496-1503, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182489

RESUMO

OBJECTIVE: There are uncertainties regarding the association between dipeptidyl peptidase 4 (DPP-4) inhibitors and bullous pemphigoid (BP), a potentially severe autoimmune skin disease. Thus, we conducted a population-based study to determine whether use of DPP-4 inhibitors, when compared with other second- to third-line antidiabetic drugs, is associated with an increased risk of BP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using the U.K. Clinical Practice Research Datalink, we conducted a cohort study among 168,774 patients initiating antidiabetic drugs between January 2007 and March 2018. Using time-dependent Cox proportional hazards models, we estimated adjusted hazard ratios (HRs) with 95% CIs of incident BP associated with current use of DPP-4 inhibitors, compared with current use of other second- to third-line antidiabetic drugs. We also conducted a propensity score-matched analysis to assess the impact of residual confounding. RESULTS: During 711,311 person-years of follow-up, 150 patients were newly diagnosed with BP (crude incidence rate, 21.1 per 100,000 person-years). Current use of DPP-4 inhibitors was associated with an increased risk of BP (47.3 vs. 20.0 per 100,000 person-years; HR 2.21 [95% CI 1.45-3.38]). HRs gradually increased with longer durations of use, reaching a peak after 20 months (HR 3.60 [95% CI 2.11-6.16]). Similar results were obtained in the propensity score-matched analysis (HR 2.40 [95% CI 1.13-4.66]). CONCLUSIONS: In this large population-based study, use of DPP-4 inhibitors was associated with an at least doubling of the risk of BP in patients with type 2 diabetes, albeit the absolute risk was low.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/efeitos adversos , Penfigoide Bolhoso/induzido quimicamente , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Fatores de Risco
19.
Expert Opin Ther Pat ; 29(7): 535-553, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31203700

RESUMO

INTRODUCTION: Dipeptidyl peptidase 4 (DPP-4) belongs to the family of serine proteases and is involved in the degradation of GLP-1 and GIP hormones, which enhance the production and release of insulin. Targeting DPP-4 inhibitors is increasingly being considered as promising paradigms to treat type 2 diabetes mellitus and therefore DPP-4 inhibitors are being considered as promising antidiabetic drugs. AREAS COVERE: This review provides an overview of published patents describing natural and synthetic DPP-4 inhibitors from January 2015 to December 2018. EXPERT OPINION: A fair number of new synthetic and natural DPP-4 inhibitors have been reported in the last four years which describe the progress in the development of various heterocyclic scaffolds or heterocyclic hybrid compounds. As a result of this, many marketed DPP-4 inhibitors that have been approved by the appropriate governing bodies during the past decade, have been introduced as inhibitors. Molecular hybridization is an emerging idea in medicinal chemistry and therefore hybrid compounds of DPP-4 inhibitors with other DPP-4 inhibitors or with antidiabetic drugs should be formulated for a comprehensive evaluation. More detailed pharmacovigilance of DPP-4 inhibitors is required because this will address the pancreas-related adverse events as well as their impact on cardiovascular outcomes via long-term studies.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Desenho de Fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Patentes como Assunto
20.
J Diabetes ; 11(12): 982-992, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31141297

RESUMO

BACKGROUND: The aim of the present study was to investigate the metabolic benefits of saxagliptin and its effects on serum bile acids (BAs) in normal weight and overweight/obese drug-naïve type 2 diabetes (T2D) patients. METHODS: In all, 282 drug-naïve T2D patients (123 normal weight [NW], with body mass index [BMI] between 19.0 and <25.0 kg/m2 ; 159 overweight/obese [OW/OB], with BMI ≥25.0 kg/m2 ) were enrolled in the study and treated with saxagliptin 5 mg daily for 24 weeks. Serum BAs were assayed by liquid chromatography with tandem mass spectrometry. RESULTS: At 24 weeks, HbA1c was significantly reduced in both groups, but the HbA1c levels were lower in the OW/OB than NW group. Moreover, significant decreases were seen at 24 weeks in C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, waist circumference, and systolic blood pressure in the OW/OB group. Interestingly, cholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) were increased in both groups after treatment, whereas chenodeoxycholic acid and deoxycholic acid (DCA) were specifically increased in the OW/OB group. Increased DCA and GDCA concentrations were significantly associated with decreased HbA1c or fasting blood glucose and CRP levels, whereas increased GDCA and GUDCA concentrations were associated with decreased waist circumference in the OW/OB group during treatment. In the NW group, increased GUDCA concentrations were significantly associated with a decrease in HbA1c. CONCLUSIONS: Type 2 diabetes patients with OW/OB exhibited greater improvement in glycemic control and additional metabolic benefits after saxagliptin treatment. Saxagliptin significantly increased the BA pool, and DCA and GDCA were associated with metabolic improvements in OW/OB T2D patients.


Assuntos
Adamantano/análogos & derivados , Ácidos e Sais Biliares/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Adulto , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , China , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Dipeptídeos/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/diagnóstico , Fatores de Tempo , Resultado do Tratamento
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