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1.
Clin Drug Investig ; 41(11): 999-1010, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34655432

RESUMO

BACKGROUND AND OBJECTIVES: Cetagliptin is a highly selective dipeptidyl peptidase-4 inhibitor under development to treat type 2 diabetes mellitus. This first-in-human study was conducted to characterise the pharmacokinetics, pharmacodynamics and tolerability of single-ascending oral doses of cetagliptin in healthy subjects. In addition, the effect of food on pharmacokinetics was evaluated. METHODS: Study 1 enrolled 66 healthy subjects in a double-blind, randomised, placebo-controlled, single-dose escalation study; sitagliptin was employed as a positive open-label control. Forty-four subjects were assigned to seven cohorts (cetagliptin 12.5, 25, 50, 100, 200, 300 or 400 mg); 12 subjects were assigned to the placebo group. The remaining ten subjects received sitagliptin 100 mg as the positive control. Blood, urine and faeces were collected for the pharmacokinetic analysis and determination of plasma dipeptidyl peptidase-4 inhibition, active glucagon-like peptide-1, glucose and insulin levels. In Study 2, 14 healthy subjects were assigned to a randomised, open-label, two-period crossover study, and received a single oral dose of cetagliptin 100 mg in the fasted state or after a high-fat meal, with a 14-day washout period between treatments. Blood samples were collected to evaluate the effects of food on the pharmacokinetics of cetagliptin. RESULTS: Following administration of a single oral dose, cetagliptin was rapidly absorbed, presenting a median time to maximum concentration of 1.0-3.25 h. The terminal half-life ranged between 25.8 and 41.3 h, which was considerably longer than that of sitagliptin. The area under the plasma concentration-time curve was approximately dose proportional between 25 mg and 400 mg, and the increase in maximum concentration was greater than dose proportional. The unchanged drug was mainly excreted in the urine (27.2-46.2% of dose) and minimally via the faeces (1.4% of dose). Dipeptidyl peptidase-4 inhibition, an increase in active glucagon-like peptide-1 and a slight decrease in blood glucose were observed, whereas insulin was not significantly altered when compared with placebo. The weighted average dipeptidyl peptidase-4 inhibition by cetagliptin 100 mg was higher than that mediated by sitagliptin 100 mg. Cetagliptin was well tolerated up to a single oral dose of 400 mg. No food effects were noted. CONCLUSIONS: Cetagliptin inhibited plasma dipeptidyl peptidase-4 activity, increased levels of active glucagon-like peptide-1 and was well tolerated at single doses up to 400 mg, eliciting no dose-limiting toxicity in healthy volunteers. Food did not affect the pharmacokinetics of cetagliptin. CLINICAL TRIAL REGISTRATION: The studies were registered at http://www.chinadrugtrials.org.cn (Nos. CTR20180167 and CTR20181331).


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Área Sob a Curva , Estudos Cross-Over , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Relação Dose-Resposta a Droga , Humanos
2.
Cochrane Database Syst Rev ; 10: CD013650, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34693515

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death globally. Recently, dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) were approved for treating people with type 2 diabetes mellitus. Although metformin remains the first-line pharmacotherapy for people with type 2 diabetes mellitus, a body of evidence has recently emerged indicating that DPP4i, GLP-1RA and SGLT2i may exert positive effects on patients with known CVD. OBJECTIVES: To systematically review the available evidence on the benefits and harms of DPP4i, GLP-1RA, and SGLT2i in people with established CVD, using network meta-analysis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and the Conference Proceedings Citation Index on 16 July 2020. We also searched clinical trials registers on 22 August 2020. We did not restrict by language or publication status. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) investigating DPP4i, GLP-1RA, or SGLT2i that included participants with established CVD. Outcome measures of interest were CVD mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, all-cause mortality, hospitalisation for heart failure (HF), and safety outcomes. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the results of searches to identify eligible studies and extracted study data. We used the GRADE approach to assess the certainty of the evidence. We conducted standard pairwise meta-analyses and network meta-analyses by pooling studies that we assessed to be of substantial homogeneity; subgroup and sensitivity analyses were also pursued to explore how study characteristics and potential effect modifiers could affect the robustness of our review findings. We analysed study data using the odds ratios (ORs) and log odds ratios (LORs) with their respective 95% confidence intervals (CIs) and credible intervals (Crls), where appropriate. We also performed narrative synthesis for included studies that were of substantial heterogeneity and that did not report quantitative data in a usable format, in order to discuss their individual findings and relevance to our review scope. MAIN RESULTS: We included 31 studies (287 records), of which we pooled data from 20 studies (129,465 participants) for our meta-analysis. The majority of the included studies were at low risk of bias, using Cochrane's tool for assessing risk of bias. Among the 20 pooled studies, six investigated DPP4i, seven studied GLP-1RA, and the remaining seven trials evaluated SGLT2i. All outcome data described below were reported at the longest follow-up duration. 1. DPP4i versus placebo Our review suggests that DPP4i do not reduce any risk of efficacy outcomes: CVD mortality (OR 1.00, 95% CI 0.91 to 1.09; high-certainty evidence), myocardial infarction (OR 0.97, 95% CI 0.88 to 1.08; high-certainty evidence), stroke (OR 1.00, 95% CI 0.87 to 1.14; high-certainty evidence), and all-cause mortality (OR 1.03, 95% CI 0.96 to 1.11; high-certainty evidence). DPP4i probably do not reduce hospitalisation for HF (OR 0.99, 95% CI 0.80 to 1.23; moderate-certainty evidence). DPP4i may not increase the likelihood of worsening renal function (OR 1.08, 95% CI 0.88 to 1.33; low-certainty evidence) and probably do not increase the risk of bone fracture (OR 1.00, 95% CI 0.83 to 1.19; moderate-certainty evidence) or hypoglycaemia (OR 1.11, 95% CI 0.95 to 1.29; moderate-certainty evidence). They are likely to increase the risk of pancreatitis (OR 1.63, 95% CI 1.12 to 2.37; moderate-certainty evidence). 2. GLP-1RA versus placebo Our findings indicate that GLP-1RA reduce the risk of CV mortality (OR 0.87, 95% CI 0.79 to 0.95; high-certainty evidence), all-cause mortality (OR 0.88, 95% CI 0.82 to 0.95; high-certainty evidence), and stroke (OR 0.87, 95% CI 0.77 to 0.98; high-certainty evidence). GLP-1RA probably do not reduce the risk of myocardial infarction (OR 0.89, 95% CI 0.78 to 1.01; moderate-certainty evidence), and hospitalisation for HF (OR 0.95, 95% CI 0.85 to 1.06; high-certainty evidence). GLP-1RA may reduce the risk of worsening renal function (OR 0.61, 95% CI 0.44 to 0.84; low-certainty evidence), but may have no impact on pancreatitis (OR 0.96, 95% CI 0.68 to 1.35; low-certainty evidence). We are uncertain about the effect of GLP-1RA on hypoglycaemia and bone fractures. 3. SGLT2i versus placebo This review shows that SGLT2i probably reduce the risk of CV mortality (OR 0.82, 95% CI 0.70 to 0.95; moderate-certainty evidence), all-cause mortality (OR 0.84, 95% CI 0.74 to 0.96; moderate-certainty evidence), and reduce the risk of HF hospitalisation (OR 0.65, 95% CI 0.59 to 0.71; high-certainty evidence); they do not reduce the risk of myocardial infarction (OR 0.97, 95% CI 0.84 to 1.12; high-certainty evidence) and probably do not reduce the risk of stroke (OR 1.12, 95% CI 0.92 to 1.36; moderate-certainty evidence). In terms of treatment safety, SGLT2i probably reduce the incidence of worsening renal function (OR 0.59, 95% CI 0.43 to 0.82; moderate-certainty evidence), and probably have no effect on hypoglycaemia (OR 0.90, 95% CI 0.75 to 1.07; moderate-certainty evidence) or bone fracture (OR 1.02, 95% CI 0.88 to 1.18; high-certainty evidence), and may have no impact on pancreatitis (OR 0.85, 95% CI 0.39 to 1.86; low-certainty evidence). 4. Network meta-analysis Because we failed to identify direct comparisons between each class of the agents, findings from our network meta-analysis provided limited novel insights. Almost all findings from our network meta-analysis agree with those from the standard meta-analysis. GLP-1RA may not reduce the risk of stroke compared with placebo (OR 0.87, 95% CrI 0.75 to 1.0; moderate-certainty evidence), which showed similar odds estimates and wider 95% Crl compared with standard pairwise meta-analysis. Indirect estimates also supported comparison across all three classes. SGLT2i was ranked the best for CVD and all-cause mortality. AUTHORS' CONCLUSIONS: Findings from both standard and network meta-analyses of moderate- to high-certainty evidence suggest that GLP-1RA and SGLT2i are likely to reduce the risk of CVD mortality and all-cause mortality in people with established CVD; high-certainty evidence demonstrates that treatment with SGLT2i reduce the risk of hospitalisation for HF, while moderate-certainty evidence likely supports the use of GLP-1RA to reduce fatal and non-fatal stroke. Future studies conducted in the non-diabetic CVD population will reveal the mechanisms behind how these agents improve clinical outcomes irrespective of their glucose-lowering effects.


Assuntos
Doenças Cardiovasculares , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Dipeptidil Peptidases e Tripeptidil Peptidases , Peptídeo 1 Semelhante ao Glucagon , Glucose , Humanos , Metanálise em Rede , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
3.
Nutr Metab Cardiovasc Dis ; 31(10): 2945-2958, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34420816

RESUMO

BACKGROUND AND AIMS: Studies of dipeptidyl peptidase inhibitors (DPP4is) report heterogeneous effects on cardiovascular targets in type 2 diabetes. This study aimed to investigate, in patients with impaired glucose tolerance (IGT), whether saxagliptin, a DPP4i, had beneficial cardiovascular effects at fasting and during the post-prandial state. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind, single-center pilot exploratory study, we included obese individuals with IGT. Twenty-four individuals (BMI 36.8 ± 4.8 kg/m2) were randomized to receive for 12 weeks either saxagliptin 5 mg a day or placebo. They were explored before and after a standardized breakfast for biological markers; microcirculatory blood flow at baseline and after transcutaneous administration of acetylcholine (Periflux System 5000® PERIMED); post-occlusive digital reactive hyperhemia (Endopat2000®); pulse wave velocity, augmentation index, central pulse pressure and subendocardial viability ratio (Sphygmocor®); cardiac hemodynamic parameters and cardiovascular autonomic nervous system activity (Task force monitor®). The results of all the investigations were similar after breakfast in the two groups at Visit 1 (acute post-prandial effects, after the first tablet) and Visit 2 (long-term post-prandial effects), and at fasting at Visit 1 and 2 (long-term effects, after 12 weeks of treatment). Only at Visit 2 the decrease in cardiac vagal activity occurring after breakfast was more sustained in the saxagliptin group than in the placebo group (interaction between treatment and time effect: p = 0.016). CONCLUSION: In obese patients with IGT, the effects of saxagliptin on the large set of cardiovascular parameters measured are neutral, except for a more marked post-prandial depression of vagal activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT01521312.


Assuntos
Adamantano/análogos & derivados , Glicemia/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Intolerância à Glucose/tratamento farmacológico , Obesidade/complicações , Período Pós-Prandial , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Sistema Cardiovascular/inervação , Sistema Cardiovascular/fisiopatologia , Dipeptídeos/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Feminino , França , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Intolerância à Glucose/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/fisiopatologia , Projetos Piloto , Fatores de Tempo , Resultado do Tratamento , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiopatologia
5.
Sci Rep ; 11(1): 16637, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404825

RESUMO

Clinical trials investigating cardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) among patients with cardiovascular and renal disease rarely recruit patients with renal impairment, despite associations with increased risk for major adverse cardiovascular events (MACE). We investigated the risk of MACE associated with the use of DPP-4i among these high-risk patients. Using a new-user, retrospective, cohort design, we analyzed 2010-2015 IBM MarketScan Commercial Claims and Encounters for patients with diabetes, comorbid with cardiovascular disease and/or renal impairment. We compared time to first MACE for DPP-4i versus sulfonylurea and versus metformin. Of 113,296 individuals, 9146 (8.07%) were new DPP-4i users, 17,481 (15.43%) were new sulfonylurea users, and 88,596 (78.20%) were new metformin users. Exposure groups were not mutually exclusive. DPP-4i was associated with lower risk for MACE than sulfonylurea (aHR 0.84; 95% CI 0.74, 0.93) and similar risk for MACE to metformin (aHR 1.07; 95% CI [1.04, 1.16]). DPP-4i use was associated with lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin. This association was most evident in the first year of therapy, suggesting that DPP-4i is a safer choice than sulfonylurea for diabetes treatment initiation in high-risk patients.


Assuntos
Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/efeitos adversos , Nefropatias/complicações , Adulto , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/efeitos adversos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico
6.
Nutr Metab Cardiovasc Dis ; 31(10): 2745-2755, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34364771

RESUMO

AIMS: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i. DATA SYNTHESIS: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure. CONCLUSIONS: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure.


Assuntos
Adamantano/análogos & derivados , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Dipeptídeos/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Fatores de Risco de Doenças Cardíacas , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Tempo , Resultado do Tratamento
7.
Diabetes Res Clin Pract ; 179: 109024, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34454002

RESUMO

AIMS: We compared cardiovascular outcomes of patients with type 2 diabetes (T2D) receiving sodium glucose cotransporter-2 inhibitors (SGLT2i) or dipeptidyl peptidase-4 inhibitors (DPP4i) under routine care. METHODS: From an administrative claims database of >5.2M citizen, we identified patients with T2D who initiated SGLT2i or DPP4i from 2014 to 2018. Patients were matched by propensity scores. The primary outcome was the 3-point major adverse cardiovascular events (3P-MACE). RESULTS: After matching, we included 3216 patients/group, with mean age of 63 years, diabetes duration of 8.7 years, and 20% had cardiovascular disease. During a median follow-up of 18 months, the rate of 3P-MACE was lower among patients who initiated SGLT2i versus DPP4i (HR 0.74; 95 %C.I. 0.58-0.94). Initiators of SGLT2i also showed significantly lower rates of myocardial infarction (HR 0.75; 95 %C.I. 0.56-1.00), hospitalization for heart failure (HR 0.44; 95 %C.I. 0.25-0.95) or cardiovascular causes (HR 0.72; 95 %C.I. 0.60-0.87), and all-cause death (HR 0.49; 95 %C.I. 0.25-0.95). Renal failure was less common with SGLT2i than with DPP4i. Results were consistent to those obtained in a meta-analysis of 10 observational studies on ~1.5M patients. CONCLUSIONS: Patients with T2D who initiated SGLT2i under routine care had better cardio-renal outcomes and lower all-cause mortality than similar patients who initiated DPP4i.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Itália , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
9.
Clin Ther ; 43(8): 1336-1355, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34304912

RESUMO

PURPOSE: Evogliptin is one of the latest dipeptidyl peptidase-4 (DPP-4) inhibitor, and a number of clinical trials have been performed following its development, including several randomized controlled trials (RCTs) performed to evaluate its efficacy and tolerability. In our study, we performed a systematic review and meta-analysis of its efficacy and tolerability by collecting RCTs and confirmed the results with Bayesian inference. Moreover, an updated quality-management system was integrated into the study process of systematic review. METHODS: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched for literature published between May 1990 and November 2020. We selected 6 homogeneous RCTs in 1017 subjects for efficacy and 1070 subjects for tolerability analysis. Regarding the efficacy profile, the mean differences from baseline (95% CIs) in hemoglobin (Hb) A1c and fasting plasma glucose (FPG) were generated as end points and derived from each study. Regarding the tolerability profile, risk ratios of adverse events (AEs), serious AEs, adverse drug reactions, and hypoglycemia were generated from baseline to outcome measurements as derived from each study. A subsequent meta-analysis was performed with Bayesian inference. FINDINGS: For HbA1c and FPG, the results suggested a statistically significant improvement with evogliptin versus placebo (HbA1c, -0.44 [95% CI, -0.54 to -0.34; P < 0.00001] and posterior median, -0.38 [95% CI, -0.51 to -0.24]; FPG, -0.61 [95% CI, -0.90 to -0.31; P < 0.0001] and posterior median, -0.48 [95% CI, -0.90 to -0.16]), but no statistically significant difference with evogliptin versus other DPP-4 inhibitors (HbA1c, -0.01 [95% CI, -0.14 to 0.12] and posterior median, -0.06 [95% CI, -0.25 to 0.12]; FPG, 0.17 [95% CI, -0.10 to 0.44] and posterior median, 0.27 [95% CI, -0.12 to 0.65]). In terms of tolerability, the overall prevalence of adverse events, including hypoglycemia, was similar between evogliptin and other DPP-4 inhibitors and placebo. IMPLICATIONS: Evogliptin appears more efficacious in terms of changes in HbA1c and FPG compared with placebo, with an efficacy comparable to those of other DPP-4 inhibitors, although with the limited data studied and the minuscule sample sizes, the predictions of posterior medians, mean differences, and risk ratios of HbA1c, FPG, and AEs by Bayesian inference were consistent with our findings through our quality-management system.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Piperazinas
10.
J Investig Med High Impact Case Rep ; 9: 23247096211033049, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34330175

RESUMO

The patient is a 69-year-old male with a past medical history of intellectual disability, hypertension, type 2 diabetes mellitus, and angiotensin-converting enzyme (ACE) inhibitor-associated angioedema who presented to the emergency department with difficulty breathing. On physical examination, the patient had significant facial edema. Nasal fiber-optic visualization revealed extensive airway edema involving the supraglottic region and the arytenoids. The patient was successfully intubated through the collective teamwork of ENT, anesthesia, and critical care teams. He was managed in the intensive care unit until recovery. Workup for markers for allergic causes of angioedema were within normal limits. Further investigation revealed that symptoms developed following the initiation of a dipeptidyl peptidase 4 (DPP-IV) inhibitor. The angiotensin-converting enzyme and DPP-IV play a significant role in the metabolism of bradykinin and substance P to their inactive metabolites. The complex interplay between the enzymes in the high-molecular-weight kininogen (HWMK) system may increase the risk of angioedema in patients with a known history of ACE inhibitor-associated angioedema when placed on a DPP-IV inhibitor. This case report highlights the pathophysiology involved.


Assuntos
Angioedema , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Idoso , Angioedema/induzido quimicamente , Angioedema/diagnóstico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Humanos , Masculino
11.
J Dermatol ; 48(10): 1584-1587, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34265108

RESUMO

Dipeptidyl peptidase 4 inhibitors (DPP-4i) are associated with an increased risk of developing bullous pemphigoid (BP) in patients with diabetes. Autoantibodies targeting epitopes on the processed BP180, 120-kDa (LAD-1), and 97-kDa (LABD97) linear immunoglobulin (Ig)A dermatosis antigens are the major autoantibodies in DPP-4i-associated BP. However, no case of mucous membrane pemphigoid (MMP) developing during treatment with DPP-4i has been reported. We report a case of MMP associated with DPP-4i. A man in his late 70s presented with oral mucous membrane erosion and a few blisters on his upper chest and back. He had used linagliptin for diabetes for over 1 year when he presented. The immunological characteristics were similar to DPP4i-associated BP: higher reactivity to LAD-1 and LABD97 than to the full-length BP180. The aphthae achieved remission after oral linagliptin was replaced with sitagliptin. However, 6 months later, the aphthae relapsed and any DPP-4i was discontinued. The aphthae disappeared, and now he is completely free from lesions associated with MMP. This case suggests that the DPP-4i may have shared roles in the production of IgG antibodies to LAD-1 or to LABD97 in the pathogenesis of DPP-4i-associated BP and MMP. Our case highlights the possibility of overlooking the mild MMP in DPP-4i-treated diabetes patients with mucosal lesions.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Penfigoide Mucomembranoso Benigno , Penfigoide Bolhoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Humanos , Linagliptina/efeitos adversos , Masculino , Membrana Mucosa , Penfigoide Mucomembranoso Benigno/diagnóstico , Penfigoide Mucomembranoso Benigno/tratamento farmacológico , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/tratamento farmacológico
12.
Diab Vasc Dis Res ; 18(3): 14791641211021585, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34182806

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular (CV) disease. In patients with T2D and established CV disease, selective inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been shown to decrease CV and all-cause mortality, and heart failure (HF) admissions. Utilising CV magnetic resonance imaging (CMR) and continuous glucose monitoring (CGM) by FreeStyle Libre Pro Sensor, we aim to explore the mechanisms of action which give Empagliflozin, an SGLT2 inhibitor, its beneficial CV effects and compare these to the effects of dipeptidyl peptidase-4 inhibitor Sitagliptin. METHODS: This is a single centre, open-label, cross-over trial conducted at the Leeds Teaching Hospitals NHS Trust. Participants are randomised for the order of treatment and receive 3 months therapy with Empagliflozin, and 3 months therapy with Sitagliptin sequentially. Twenty-eight eligible T2D patients with established ischaemic heart disease will be recruited. Patients undergo serial CMR scans on three visits. DISCUSSION: The primary outcome measure is the myocardial perfusion reserve in remote myocardium. We hypothesise that Empaglifozin treatment is associated with improvements in myocardial blood flow and reductions in myocardial interstitial fibrosis, independent of CGM measured glycemic control in patients with T2D and established CV disease. TRIAL REGISTRATION: This study has full research ethics committee approval (REC: 18/YH/0190) and data collection is anticipated to finish in December 2021. This study was retrospectively registered at https://doi.org/10.1186/ISRCTN82391603 and monitored by the University of Leeds. The study results will be submitted for publication within 6 months of completion.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Circulação Coronária/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Controle Glicêmico , Isquemia Miocárdica/tratamento farmacológico , Fosfato de Sitagliptina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inglaterra , Fibrose , Glucosídeos/efeitos adversos , Controle Glicêmico/efeitos adversos , Humanos , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/fisiopatologia , Miocárdio/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fosfato de Sitagliptina/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
14.
Prim Care Diabetes ; 15(5): 761-771, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33926837

RESUMO

AIM/OBJECTIVE: Recently, the glucagon-like peptide-1 receptor agonists (GLP-1RA) class showed a significant reduction in heart failure (HF) hospitalization in several meta-analyses of cardiovascular outcome trials (CVOTs). The objective of this systematic review is to summarize the real-world evidence regarding HF outcomes of GLP-1RAs. METHODS: We searched the PubMed and EMBASE databases for observational studies that investigated HF outcomes of GLP-1RAs. RESULTS: Our search yielded 10 observational studies. Of those, 7 were cohort studies, and 3 were nested case-control studies. The risk of HF was the outcome in four cohort studies. One study that compared exenatide and exenatide combined with insulin to insulin showed a reduction in HF risk in the exenatide and exenatide plus insulin groups (HR 0.34, 95% CI 0.22-0.52, p-value <0.001 and HR 0.40, 95% CI 0.32-0.50, p-value <0.001, respectively). The other three cohort studies did not show a statistically significant result. In the three cohort studies that investigated HF hospitalization as an outcome, two showed a lower rate of HF hospitalization [48 (16.7%) vs. 76 (28%), p-value <0.05 and HR 0.51, 95% CI 0.34-0.77, p = 0.002] in the GLP-1RA groups. Conversely, the remaining study showed a reduction of 14% in HF hospitalization in the dipeptidyl peptidase-4 inhibitors (DPP-4i) group compared to the GLP-1RA group (HR 0.86, 95% CI 0.83-0.90). In contrast to the cohort studies, the three nested case-control studies showed similar results of no association of GLP-1RA use and HF hospitalization with OR 0.67 (95% CI 0.32-1.42), HR 0.95 (95% CI 0.83-1.10), and OR 0.84 (95% CI 0.48-1.47), respectively. CONCLUSION: The real-world evidence regarding the reduction in HF risk and hospitalization in GLP-1RA users is conflicting. Further well-designed, large multicenter, observational studies are needed to show clearer evidence.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Insuficiência Cardíaca , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1 , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Humanos , Hipoglicemiantes/efeitos adversos , Estudos Multicêntricos como Assunto
15.
Expert Opin Drug Metab Toxicol ; 17(6): 725-731, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33899649

RESUMO

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have significant clinical efficacy for type 2 diabetes mellitus (T2DM). The combination of fotagliptin (FOT) with metformin (MET) is a promising therapeutic approach in MET-resistant patients. The aim of the present study was to evaluate the pharmacokinetic (PK) interaction between FOT and MET in healthy subjects after multiple-dose administration. METHODS: Eighteen participants received a randomized open-label, three period treatment that included MET 1000 mg alone, co-administration of FOT 24 mg and MET, followed by FOT 24 mg alone. Serial blood samples were collected for PK analysis, which included geometric mean ratios (GMRs) with 90% confidence intervals (CIs), area under the concentration-time curve (AUC), and maximum plasma concentration (Cmax). RESULTS: Analysis results showed that for FOT alone or combination therapy, the 90% CIs of the GMR for AUC0-24,ss and Cmax,ss were 102.08% (98.9%, 105.36%) and 110.65% (102.19%, 119.82%), respectively. For MET, they were 113.41% (100.32%, 128.22%) and 97.11% (83.80%, 112.55%) for AUC0-12,ss and Cmax,ss, respectively. FOT or MET monotherapy and the combination therapy with both drugs were well tolerated. CONCLUSIONS: No PK drug-drug interactions were found in the combination therapy with FOT and MET. Therefore, FOT can be co-administered with MET without dose adjustment. TRIAL REGISTRATION: The trial is registered at http://www.chinadrugtrials.org.cn/(Registration No. CTR20190221).


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Piperidinas/farmacocinética , Triazinas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Interações Medicamentosas , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Adulto Jovem
17.
Expert Opin Pharmacother ; 22(16): 2149-2165, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33823723

RESUMO

INTRODUCTION: An increasing number of older patients has type 2 diabetes treated with different oral antidiabetic agents whose safety may raise concern considering some particularities of a heterogeneous elderly population. AREAS COVERED: This article discusses some characteristics of older patients that could increase the risk of adverse events, with a focus on hypoglycemia. It describes the most frequent and/or severe complications reported in the elderly in both randomized controlled trials and observational studies with metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium-glucose cotransporter type 2 inhibitors (gliflozins). EXPERT OPINION: Old patients may present comorbidities (renal impairment, vascular disease, heart failure, risk of dehydration, osteoporosis, cognitive dysfunction) that could increase the risk of severe adverse events. Sulfonylureas (and meglitinides) induce hypoglycemia, which may be associated with falls/fractures and cardiovascular events. Medications lacking hypoglycemia should be preferred. Gliptins appear to have the best tolerance/safety profile whereas gliflozins exert a cardiorenal protection. However, data are lacking in very old or frailty old patients so that caution and appropriate supervision of such patients are required. Taking advantage of a large choice of pharmacotherapies, personalized treatment is recommended based upon both drug safety profiles and old patient individual characteristics.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos
18.
Rinsho Shinkeigaku ; 61(5): 329-331, 2021 May 19.
Artigo em Japonês | MEDLINE | ID: mdl-33867418

RESUMO

There have been a few reports on Dipeptidyl peptidase (DPP)-4 inhibitor-induced dropped head syndrome. However, there has been no known report on temporal changes in MRI findings. The patient described here was a 63-year-old man who was prescribed oral sitagliptin (50 mg/day) in February 2019. He experienced a dropped head from mid-January 2020, and in early April that year, he was admitted to our hospital for further evaluation. Weakness of the cervical extensor muscles (MMT 3) was noted, and MRI findings showed that the posterior cervical muscle group was hyperintense on short inversion time inversion recovery (STIR). We suspected sitagliptin to be the cause of his dropped head and discontinued it. On the 10th day of admission, his posture improved to the median position. One month after discontinuation of sitagliptin, MRI findings showed an improvement in the STIR hyperintensity of the posterior cervical muscle. In conclusion, if the initiation of a DPP-4 inhibitor results in dropped head syndrome, discontinuation of the drug should be considered.


Assuntos
Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Cabeça , Debilidade Muscular/induzido quimicamente , Doenças Musculares/induzido quimicamente , Músculos do Pescoço , Postura , Fosfato de Sitagliptina/efeitos adversos , Administração Oral , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Cabeça/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Músculos do Pescoço/diagnóstico por imagem , Fosfato de Sitagliptina/administração & dosagem , Síndrome , Suspensão de Tratamento
19.
Clin Pharmacol Ther ; 110(2): 464-472, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33866549

RESUMO

This study assessed the effects of dipeptidyl peptidase-4 inhibitors (DPP4is) vs. sulfonylureas (SUs) on composite renal, cardiovascular, and hospitalized hypoglycemia outcomes in type 2 diabetes (T2D) patients with advanced chronic kidney disease (CKD) who were underrepresented in previous clinical studies. The National Health Insurance Research Database was utilized. Patients with T2D and advanced CKD (stages 3b-5) with stable use of DPP4is or SUs were identified during 2011-2015 and followed until death or December 31, 2016. The primary outcome was the composite renal outcome. Secondary outcomes included hospitalized heart failure (HHF), major adverse cardiovascular event (MACE), hospitalized hypoglycemia, and all-cause death. Subdistribution hazard models were employed to assess treatment effects on clinical outcomes. A total of 1,204 matched pairs of DPP4i and SU users were analyzed. Compared with SUs, DPP4is had no significant difference in the risks of the composite renal outcome, HHF, and three-point and four-point MACE (hazard ratios (95% confidence intervals): 1.10 (0.93-1.31), 1.11 (0.95-1.30), 0.97 (0.79-1.19), and 1.08 (0.94-1.24), respectively), but reduced risks of hospitalized hypoglycemia (0.53 (0.43-0.64)) and all-cause death (0.71 (0.53-0.96)). In conclusion, among patients with T2D and advanced CKD, the use of DPP4is vs. SUs was associated with comparable safety profiles on renal and cardiovascular outcomes, and reduced risks of hospitalized hypoglycemia and all-cause death. DPP4is may be preferred for patients with T2D and advanced CKD, and the regular monitoring on cardiac function remains crucial among this population who are at a higher risk of HHF.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/efeitos adversos , Nefropatias/induzido quimicamente , Insuficiência Renal Crônica/complicações , Compostos de Sulfonilureia/efeitos adversos , Adulto , Estudos de Coortes , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/mortalidade , Estudos Retrospectivos , Medição de Risco , Taiwan/epidemiologia , Resultado do Tratamento
20.
Int J Med Sci ; 18(9): 1946-1952, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33850463

RESUMO

Background: The world's first Diabetes Medications (Insulin) was marketed in October 1923. Some studies suggested the association of diabetes medications with Bullous Pemphigoid (BP), especially the Dipeptidyl Peptidase 4 (DPP-4) inhibitors. The study aims to detect an association between diabetes medications (focusing on DPP-4 inhibitors) and bullous pemphigoid based on FDA Adverse Event Reporting System (FAERS). Methods: All spontaneous reports of diabetes medications inhibitors-related BP recorded in the FAERS between March 2004 and August 2020 were included in the present study. Disproportionality analysis was performed to find the signal between diabetes medications and BP. The Chi-Squared with Yates' correction (χ2 Yates), proportional reporting ratio (PRR) and the lower limit of the 95% confidence interval of the Reporting Odds Ratio (ROR025) were calculated as a measure. A signal was detected when ROR025 > 1, PRR > 2, χ2 Yates > 4 and at least 3 cases. Results: There were 3770 reports for BP in FAERS. The strongest signal for diabetes medications-BP association were DDP-4 inhibitors (ROR025: 13.700, PRR: 15.408), followed by Meglitinides (ROR025: 12.708, PRR: 16.777), Non-sulfonylureas (ROR025: 6.434, PRR: 7.016), Alpha-glucosidase inhibitors (ROR025: 6.105, PRR: 10.738), Sulfonylureas (ROR025:2.655, PRR: 3.200). Conclusions: This study detected a strong signal between BP and DDP-4 inhibitors, alpha-glucosidase inhibitors, meglitinides, non-sulfonylureas, and sulfonylureas in FAERS. The signal was significantly higher with alogliptin than with the other DPP-4 inhibitors. The study doesn't suggest the association between the incretin mimetics, insulin, SGLT-2 inhibitors, thiazolidinediones and BP in FAERS.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Penfigoide Bolhoso/epidemiologia , Adulto , Idoso , Benzamidas/efeitos adversos , Estudos de Casos e Controles , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Inibidores de Glicosídeo Hidrolases/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/induzido quimicamente , Farmacovigilância , Estudos Retrospectivos , Compostos de Sulfonilureia/efeitos adversos , Estados Unidos/epidemiologia , United States Food and Drug Administration/estatística & dados numéricos
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