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1.
Artigo em Inglês | MEDLINE | ID: mdl-36379585

RESUMO

INTRODUCTION: Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin. RESEARCH DESIGN AND METHODS: This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500-1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52-85 mmol/mol (7.0%-9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects. RESULTS: This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy. CONCLUSIONS: This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D. TRIAL REGISTRATION NUMBER: jRCT1011220005.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Humanos , Metformina/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada/análise , Controle Glicêmico , Estudos Prospectivos , Quimioterapia Combinada , Resultado do Tratamento , Hipoglicemiantes/uso terapêutico , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
2.
PLoS One ; 17(11): e0271574, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36395143

RESUMO

BACKGROUND: While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size. METHODS: Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome. RESULTS: 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation (RR 0.68, 0.32-1.44), and mortality (RR 0.82, 0.41-1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28-0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33-0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control. CONCLUSIONS: There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Adulto , Criança , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Estudos Retrospectivos , COVID-19/tratamento farmacológico , RNA Viral/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento , Compostos de Sulfonilureia/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Metformina/uso terapêutico , Estudos de Coortes
3.
Cardiovasc Diabetol ; 21(1): 248, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36397062

RESUMO

BACKGROUND: The reno-protective effect of second-line treatments in type 2 diabetes has been assessed by clinical trials but generalizability to routine clinical practice is still uncertain. We aimed to assess the effectiveness of these treatments, when added to metformin, on the risk of chronic kidney disease (CKD). METHODS: A real-world, hospital-based, type 2 diabetes cohort was retrospectively assembled at Ramathibodi Hospital from 2010 to 2019. Patients who received sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as second-line antihyperglycemic treatment were included. Treatment effect models with inverse probability weighting and regression adjustment were used to estimate CKD risk according to treatment. RESULTS: CKD was identified in 4,132 of the 24,777 patients with type 2 diabetes (16.7%). The CKD incidence (95% CI) was 4.1% (2.2%, 6.9%), 13.5% (12.5%, 14.6%), 14.8% (13.5%, 16.1%), and 18.0% (17.4%, 18.5%) for patients receiving SGLT2i, DPP4i, TZD, and SU treatment, respectively. The average treatment effects (i.e., the difference in CKD risk) for SGLT2i, DPP4i, and TZD compared to SU were - 0.142 (- 0.167, - 0.116), - 0.046 (- 0.059, - 0.034), and - 0.004 (- 0.023, 0.014), respectively, indicating a significant reduction in CKD risk of 14.2% and 4.6% in the SGLT2i and DPP4i groups, respectively, compared to the SU group. Furthermore, SGLT2i significantly reduced CKD risk by 13.7% (10.6%, 16.8%) and 9.5% (6.8%, 12.2%) when compared to TZD and DPP4i, respectively. CONCLUSIONS: Our study identified 14.2%, 13.7%, and 9.5% reduced CKD risk in Thai patients with type 2 diabetes who were treated with SGLT2i compared to those treated with SU, TZD, and DPP4i, respectively, in real-world clinical data. Previous evidence of a reno-protective effect of SGLT2i reported in other populations is consistent with our observations in this Southeast Asian cohort.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Tiazolidinedionas , Humanos , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Estudos Retrospectivos , Tailândia/epidemiologia , Resultado do Tratamento , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Tiazolidinedionas/uso terapêutico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Hospitais
4.
BMJ ; 379: e071380, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36318979

RESUMO

OBJECTIVE: To determine whether the use of glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, separately, is associated with a decreased risk of exacerbations of chronic obstructive pulmonary disease among patients with chronic obstructive pulmonary disease and type 2 diabetes. DESIGN: Population based cohort study using an active comparator, new user design. SETTING: The United Kingdom Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases. PARTICIPANTS: Three active comparator, new user cohorts of patients starting the study drugs (GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT-2 inhibitors) or sulfonylureas with a history of chronic obstructive pulmonary disease. The first cohort included 1252 patients starting GLP-1 receptor agonists and 14 259 starting sulfonylureas, the second cohort included 8731 patients starting DPP-4 inhibitors and 18 204 starting sulfonylureas, and the third cohort included 2956 patients starting SGLT-2 inhibitors and 10 841 starting sulfonylureas. MAIN OUTCOME MEASURES: Cox proportional hazards models with propensity score fine stratification weighting were fitted to estimate hazard ratios and 95% confidence intervals of severe exacerbation of chronic obstructive pulmonary disease (defined as hospital admission for chronic obstructive pulmonary disease), separately for GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Whether these drugs were associated with a decreased risk of moderate exacerbation (defined as a co-prescription of an oral corticosteroid and an antibiotic along with an outpatient diagnosis of acute chronic obstructive pulmonary disease exacerbation on the same day) was also assessed. RESULTS: Compared with sulfonylureas, GLP-1 receptor agonists were associated with a 30% decreased risk of severe exacerbation (3.5 v 5.0 events per 100 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and moderate exacerbation (0.63, 0.43 to 0.94). DPP-4 inhibitors were associated with a modestly decreased incidence of severe exacerbation (4.6 v. 5.1 events per 100 person years; hazard ratio 0.91, 0.82 to 1.02) and moderate exacerbation (0.93, 0.82 to 1.07), with confidence intervals including the null value. Finally, SGLT-2 inhibitors were associated with a 38% decreased risk of severe exacerbation (2.4 v 3.9 events per 100 person years; hazard ratio 0.62, 0.48 to 0.81) but not moderate exacerbation (1.02, 0.83 to 1.27). CONCLUSIONS: In this population based study, GLP-1 receptor agonists and SGLT-2 inhibitors were associated with a reduced risk of severe exacerbations compared with sulfonylureas in patients with chronic obstructive pulmonary disease and type 2 diabetes. DPP-4 inhibitors were not clearly associated with a decreased risk of chronic obstructive pulmonary disease exacerbations.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Doença Pulmonar Obstrutiva Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Estudos de Coortes , Compostos de Sulfonilureia/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
5.
Front Endocrinol (Lausanne) ; 13: 1028114, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339443

RESUMO

Previous studies have reported that dual drug combinations consisting of γ-aminobutyric acid (GABA) together with a dipeptidyl-peptidase-4 inhibitor (DPP-4i), also a DPP-4i with a proton pump inhibitor (PPI), could improve pancreatic ß-cell function and ameliorate diabetes in diabetic mice. In this study, we sought to determine if a triple drug combination of GABA, a DPP-4i and a PPI might have superior therapeutic effects compared with double drug therapies in the prevention and reversal of diabetes in the non-obese diabetic (NOD) mouse model of human type 1 diabetes (T1D). In a diabetes prevention arm of the study, the triple drug combination of GABA, a DPP-4i, and a PPI exhibited superior therapeutic effects in preventing the onset of diabetes compared with all the double drug combinations and placebo. Also, the triple drug combination significantly increased circulating C-peptide and serum insulin levels in the mice. In a diabetes reversal arm of the study, the triple drug combination was superior to all of the double drug combinations in reducing hyperglycemia in the mice. In addition, the triple drug combination was the most effective in increasing circulating levels of C-peptide and serum insulin, thereby significantly reducing exogenous insulin needs. The combination of GABA, a DPP-4i and a PPI appears to be a promising and easily scalable therapy for the treatment and prevention of T1D.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Inibidores da Dipeptidil Peptidase IV , Animais , Camundongos , Peptídeo C , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico , Hipoglicemiantes/uso terapêutico , Camundongos Endogâmicos NOD , Omeprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico
6.
Front Endocrinol (Lausanne) ; 13: 1003263, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36353233

RESUMO

Objective: To analyze the efficacy and safety of three novel hypoglycemic agents, glucagon-like peptidyl-1 receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4i), and sodium-glucose cotransporter two inhibitors (SGLT2i) in type 2 diabetes mellitus (T2DM) patients with severe chronic kidney disease (CKD) (defined in this study as CKD stage 3 B or above, eGFR< 45 mL/min/1.73 m²) based on important RCTs to date. Methods: We retrieved studies published before April 15, 2022, from EMBASE, PubMed/MEDLINE, Cochrane Library and included randomized controlled trials in which the participants were patients with T2DM and severe CKD. Frequentist methods were used in the network meta-analysis. Results: Nineteen studies of 17 trials involving 6,607 participants met our inclusion criteria. Compared with placebo and DPP-4i, SGLT2i demonstrated a significantly lower incidence of serious renal-related adverse events or renal death, and the odds ratios (OR) were 0.69 (0.58, 0.81) and 0.63 (0.40, 1.00), respectively. Compared with placebo, SGLT2i significantly reduced the incidence of all-cause death and severe AE; the ORs were 0.72 (0.55, 0.94) and 0.65 (0.47, 0.91), respectively. Compared with placebo, DPP-4i significantly reduced the level of HbA1c, and the difference between mean changes from baseline was -0.36 (-0.63, -0.09). Conclusions: Patients with T2DM complicated by severe CKD may benefit from SGLT2i. SGLT2i can reduce the incidence of serious renal-related AEs or renal death, as well as severe side effects, and has a positive effect on the patient's renal function and survival, even for only CKD patients can also be considered. GLP-1 RAs can be used as a supplement if blood sugar control is poor. For dialysis patients, DPP-4i can assist blood glucose control, reduce insulin dosage, and reduce the risk of hypoglycemia. Systematic review registration: INPLASY https://inplasy.com/inplasy-2021-12-0106/, identifier INPLASY2021120106.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Inibidores da Dipeptidil Peptidase IV , Insuficiência Renal Crônica , Humanos , Hipoglicemiantes/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metanálise em Rede , Hemoglobina A Glicada/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
7.
Biochem Biophys Res Commun ; 635: 84-91, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36265286

RESUMO

Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Linagliptina , Animais , Masculino , Camundongos , Adenosina , Albuminas , Dinoprostona , Hemodinâmica , Insulina , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Natriurese , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico
9.
Front Endocrinol (Lausanne) ; 13: 994944, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36313782

RESUMO

Aims: Hyperglucagonemia occurs in the pathogenesis of type 2 diabetes mellitus (T2DM). In this meta-analysis, we summarized the effects of DPP4 inhibitors on glucagon levels in patients with T2DM. Materials and methods: Randomized controlled trials (RCTs) comparing the influence of DPP4 inhibitors on circulating glucagon levels with placebo or other oral antidiabetic drugs (OADs) in patients with T2DM were identified by searches of Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library). Only studies reporting changes in glucagon level presented as total area under the curve (AUCglucagon) using a meal or oral glucose tolerance test were included. Results were combined using a random-effects model that incorporated potential heterogeneity among the included studies. Results: A total of 36 RCTs with moderate to high quality were included. Overall, the numbers of T2DM patients included for the meta-analyses comparing DPP4 inhibitors with placebo and other OADs were 4266 and 1652, respectively. Compared to placebo, DPP4 inhibitors significantly reduced circulating glucagon levels (standard mean difference [SMD]: -0.32, 95% CI: -0.40 to -0.24, P<0.001; I2 = 28%). Analysis of subgroups revealed that study characteristics had no significant effect on results, such as study design (parallel group or crossover), number of patients, mean patient age, proportion of men, baseline HbA1c, duration of diabetes, background therapy, treatment duration, or methods for glucagon measurement (all P for subgroup differences >0.05). Moreover, DPP4 inhibitors significantly reduced glucagon levels compared to other OADs (SMD: -0.35, 95% CI: -0.53 to -0.16, P<0.001; I2 = 66%), and the reduction in glucagon was greater in comparison with insulin secretagogues than in comparison with non-insulin secretagogues (P for subgroup difference =0.03). Systematic review registration: https://inplasy.com/, identifier INPLASY202280104. Conclusions: DPP4 inhibitors are effective at reducing the circulating postprandial glucagon level in T2DM patients.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Masculino , Humanos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glucagon , Secretagogos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico
10.
Atherosclerosis ; 360: 1-7, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36191453

RESUMO

BACKGROUND AND AIMS: Anti-atherosclerotic effects of early intervention with dipeptidyl peptidase-4 inhibitors remain poorly defined. METHODS: In a prospective, single-center, randomized trial, 66 patients with acute coronary syndrome (ACS) and mild dysglycemia (HbA1c 6.0 (5.7, 6.3)%, 58% of impaired glucose tolerance) were randomly assigned to receive alogliptin (n = 33) or placebo (n = 33) in addition to standard treatments. Serial intravascular ultrasound (IVUS) was performed at baseline and 10 months to evaluate changes in coronary percent plaque volumes (%PV) and plaque tissue components of non-culprit lesions (NCLs). RESULTS: Baseline clinical and IVUS characteristics, as well as decreases in HbA1c and lipid variables during 10 months, did not differ significantly between the 2 groups. In contrast, with respect to vascular responses, the alogliptin group showed significantly greater decreases in plaque volumes (-0.3 ± 0.6 vs. -0.04 ± 0.7 mm3/mm, p = 0.03) and %PV (-0.9 ± 2.8 vs. 1.2 ± 3.6%, p = 0.01), with a tendency toward smaller lumen loss (-0.1 ± 0.7 vs. -0.4 ± 0.8 mm3/mm, p = 0.07) compared with the placebo group. Significantly decreased percent necrotic volumes (%NV) (-1.9 ± 3.8 vs. 0.3 ± 3.7%, p = 0.03) and increased fibrotic volumes (2.5 ± 5.0 vs. -0.3 ± 5.3%, p = 0.05) were or tended to be seen in alogliptin versus placebo groups at 10 months. In multiple regression analysis, alogliptin use was a statistically significant determinant of changes in %PV (ß = -0.33, p = 0.004) and %NV (ß = -0.28, p = 0.03) at 10 months. CONCLUSIONS: Alogliptin treatment, independently of glycemic and lipid status, resulted in significant plaque regression and stabilization in NCLs in patients with ACS and mild dysglycemia, suggesting the potential utility of early intervention with incretin-based treatments for this patients' subset.


Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Inibidores da Dipeptidil Peptidase IV , Placa Aterosclerótica , Humanos , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/patologia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/patologia , Hemoglobina A Glicada , Incretinas , Lipídeos , Estudos Prospectivos , Ultrassonografia de Intervenção , Inibidores da Dipeptidil Peptidase IV/uso terapêutico
13.
J Med Chem ; 65(20): 13946-13966, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36201615

RESUMO

The management of patients with type 2 diabetes mellitus (T2DM) is shifting from cardio-centric to weight-centric or, even better, adipose-centric treatments. Considering the downsides of multidrug therapies and the relevance of dipeptidyl peptidase IV (DPP IV) and carbonic anhydrases (CAs II and V) in T2DM and in the weight loss, we report a new class of multitarget ligands targeting the mentioned enzymes. We started from the known α1-AR inhibitor WB-4101, which was progressively modified through a tailored morphing strategy to optimize the potency of DPP IV and CAs while losing the adrenergic activity. The obtained compound 12 shows a satisfactory DPP IV inhibition with a good selectivity CA profile (DPP IV IC50: 0.0490 µM; CA II Ki 0.2615 µM; CA VA Ki 0.0941 µM; CA VB Ki 0.0428 µM). Furthermore, its DPP IV inhibitory activity in Caco-2 and its acceptable pre-ADME/Tox profile indicate it as a lead compound in this novel class of multitarget ligands.


Assuntos
Anidrases Carbônicas , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Humanos , Dipeptidil Peptidase 4 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/uso terapêutico , Células CACO-2 , Ligantes , Adrenérgicos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/farmacologia
14.
J Manag Care Spec Pharm ; 28(11): 1253-1259, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36282929

RESUMO

BACKGROUND: Although metformin is generally universally recommended as a first-line pharmacologic therapy for most people living with type 2 diabetes, second-line and third-line choices can require a tailored approach to achieve optimal blood glucose and glycated hemoglobin levels. OBJECTIVE: To examine national trends in second- and third-line antihyperglycemic medications following metformin monotherapy, comparing 2015 and 2019. METHODS: This retrospective cohort analysis of deidentified pharmacy claims from a large national pharmacy benefits manager from January 1, 2015, to December 31, 2015, and again in January 1, 2019, to December 31, 2019, included adults (aged ≥ 18 years) continuously enrolled in commercial or Medicare insurance plans who filled an index metformin prescription in either year. Proportions of patients by second-line and third-line antihyperglycemic class were calculated. RESULTS: Second-line use of sulfonylureas (-10.1%; P < 0.001), combination drugs (-3.0%; P < 0.001), and dipeptidyl peptidase-4 inhibitors (-2.0%; P = 0.031) significantly declined, whereas second-line use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) (+4.9%; P < 0.001) and glucagon-like peptide-1 receptor agonists (GLP-1Ras) (+10.0%; P < 0.001) significantly increased. Similarly, third-line use of sulfonylureas declined (-5.5%; P = 0.005), whereas third-line use of SGLT2is (+3.4%; P = 0.005) and GLP-1RAs (+8.3%; P < 0.001) increased. Similar trends between 2015 and 2019 were found in commercial and Medicare subgroups. Among all groups in 2015 compared with 2019, sulfonylureas were the most prescribed second-line class and insulins the most common third-line class. Although SGLT2i and GLP-1RA together represented more than one-third of second-line and third-line prescriptions for commercially insured patients in 2019 (34.3% and 35.0%, respectively), these classes were less frequently prescribed in the Medicare subgroup (18% and 25.6%, respectively). CONCLUSIONS: This report provides updated second-line and third-line antihyperglycemic medication prescribing trends in the United States, which suggests that evidence-based guidelines are being used in practice to prevent complications and individualize diabetes care. DISCLOSURES: Ms Swart and Drs Peasah and Good are employed by UPMC Health Plan. Dr Neilson was employed by UPMC Health Plan at the time of the study. Drs Munshi and Henderson were employed by Evernorth at the time of the study.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Adulto , Humanos , Idoso , Estados Unidos , Metformina/uso terapêutico , Glicemia , Hemoglobina A Glicada/análise , Receptor do Peptídeo Semelhante ao Glucagon 1 , Estudos Retrospectivos , Medicare , Hipoglicemiantes/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Sódio/análise , Sódio/uso terapêutico
15.
BMC Endocr Disord ; 22(1): 251, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36261824

RESUMO

BACKGROUND: Safety of sulfonylurea drugs in the treatment of Type 2 Diabetes is still under debate. The aim of this study was to compare the all-cause mortality and cardiovascular adverse events of sulfonylureas and drugs with a low risk for hypoglycaemia in adults with type 2 diabetes. METHODS: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: MEDLINE (PubMed, OVID), Embase, Cochrane Central Register of Controlled Trials, CINAHL, WOS and Lilacs. STUDY SELECTION: Randomised controlled head-to-head trials that compared sulfonylureas with active control with low hypoglycaemic potential in adults (≥ 18 years old) with type 2 diabetes published up to August 2015. The drug classes involved in the analysis were metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. OUTCOMES: The primary endpoint was all-cause mortality. The secondary endpoints were MACE, cardiovascular events and severe hypoglycaemia. SYNTHESIS OF RESULTS: Two reviewers checked study eligibility, independently extracted data and assessed quality with disagreements resolved through discussion. We assessed the risk of bias of the included studies using the Cochrane risk of bias tool for randomized trials v2. Pooled odds ratios (ORs) were estimated by using fixed effects model. The study is registered on PROSPERO (26/05/2016 CRD42016038780). RESULTS: Our final analysis comprised 31 studies (26,204 patients, 11,711 patients given sulfonylureas and 14,493 given comparator drugs). In comparison to drugs with low hypoglycaemic potential, sulfonylureas had higher odds for all-cause mortality (OR 1.32, 95% CI 1.00-1.75), MACE (OR 1.32, 95% CI 1.07-1.61), myocardial infarction (fatal and non-fatal) (OR 1.67, 95% CI 1.17-2.38) and hypoglycaemia (OR 5.24, 95% CI 4.20-6.55). Subsequent sensitivity analysis revealed differences in the effect of sulfonylureas, with an increased risk of all-cause mortality with glipizide but not the other molecules. CONCLUSION: Our meta-analysis raises concern about the safety of SUs compared to alternative drugs involved in current analysis. Important differences may exist within the drug class, and glimepiride seems to have best safety profile.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Hipoglicemia , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Adulto , Humanos , Adolescente , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Glipizida/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Metformina/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/complicações , Peptídeo 1 Semelhante ao Glucagon , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Simportadores/uso terapêutico , Glucose , Sódio
16.
PLoS One ; 17(10): e0269414, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36251654

RESUMO

BACKGROUND: Cardiovascular and renal benefits of sodium glucose co-transporter 2 inhibitors (SGLT2i) have been clearly demonstrated. However, studies comparing the effects of dapagliflozin and empagliflozin are scarce. In addition, relatively few studies have analyzed the effects of SGLT2i in diabetic patients without established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF), and current guidelines recommend SGLT2i and other antidiabetic drugs equally in this population. Therefore, we aimed to compare the clinical outcomes between dapagliflozin, empagliflozin, and dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with type 2 diabetes without prior ASCVD, CKD, or HF. METHODS: Using a propensity-score matching method, we retrospectively analyzed 921 patients treated with dapagliflozin, 921 patients treated with empagliflozin, and 1842 patients treated with DPP4i (control group). Study outcomes comprised composite coronary events (acute coronary syndrome and coronary revascularization), composite ischemic events (coronary events and stroke), and composite heart failure and renal events. RESULTS: During follow up (median, 43.4 months), the incidence of composite coronary events was significantly lower in the SGLT2i groups than in the control group, and the incidence of composite ischemic events was lower in the dapagliflozin group than in the control group. Dapagliflozin and empagliflozin both demonstrated significant benefits in terms of HF and renal outcomes, supported by renoprotective effects, as assessed by the change in glomerular filtration rate. At 24-36 months of treatment, the empagliflozin group had higher low-density lipoprotein cholesterol levels, and lower glycated hemoglobin levels, compared to those in the dapagliflozin and control groups. CONCLUSION: SGLT2i use was associated with a significantly reduced risk of ASCVD, HF hospitalization, and renal events, compared to that with DPP4i use among diabetic patients without prior ASCVD, CKD, or HF. There were no significant differences in clinical outcomes between dapagliflozin and empagliflozin, supporting a SGLT2i class effect.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Insuficiência Cardíaca , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/complicações , Colesterol , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos , Hemoglobina A Glicada/análise , Insuficiência Cardíaca/complicações , Hipoglicemiantes/uso terapêutico , Lipoproteínas LDL , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
17.
Front Endocrinol (Lausanne) ; 13: 1012412, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36267570

RESUMO

Background: In contrast to Western population, glucagon-like peptide-1 (GLP-1) levels are preserved in some East Asian population with type 2 diabetes (T2D), explaining why dipeptidyl peptidase-IV (DPP-IV) inhibitors are more effective in East Asians. We assessed whether differences in endogenous GLP-1 levels resulted in different treatment responses to DPP-IV inhibitors in prediabetes and T2D. Methods: A prospective 12-week study using linagliptin 5mg once daily in 50 subjects (28 prediabetes and 22 T2D) who were stratified into high versus low fasting GLP-1 groups. A 75-g oral glucose tolerance test (OGTT) was performed at week 0 and 12. Primary outcomes were changes in HbA1c, fasting and post-OGTT glucose after 12 weeks. Secondary outcomes included changes in insulin resistance and beta cell function indices. Results: There was a greater HbA1c reduction in subjects with high GLP-1 compared to low GLP-1 levels in both the prediabetes and T2D populations [least-squares mean (LS-mean) change of -0.33% vs. -0.11% and -1.48% vs. -0.90% respectively)]. Linagliptin significantly reduced glucose excursion by 18% in high GLP-1 compared with 8% in low GLP-1 prediabetes groups. The reduction in glucose excursion was greater in high GLP-1 compared to low GLP-1 T2D by 30% and 21% respectively. There were significant LS-mean between-group differences in fasting glucose (-0.95 mmol/L), 2-hour glucose post-OGTT (-2.4 mmol/L) in the high GLP-1 T2D group. Improvement in insulin resistance indices were seen in the high GLP-1 T2D group while high GLP-1 prediabetes group demonstrated improvement in beta cell function indices. No incidence of hypoglycemia was reported. Conclusions: Linagliptin resulted in a greater HbA1c reduction in the high GLP-1 prediabetes and T2D compared to low GLP-1 groups. Endogenous GLP-1 level play an important role in determining the efficacy of DPP-IV inhibitors irrespective of the abnormal glucose tolerance states.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Resistência à Insulina , Estado Pré-Diabético , Humanos , Peptídeo 1 Semelhante ao Glucagon , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Linagliptina/uso terapêutico , Hemoglobina A Glicada , Estado Pré-Diabético/tratamento farmacológico , Estudos Prospectivos , Glicemia , Dipeptidil Peptidases e Tripeptidil Peptidases
19.
Medicina (Kaunas) ; 58(10)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36295543

RESUMO

Background and objectives: In the last couple of years, pharmacological management of patients with type 2 diabetes mellitus (T2DM) have been markedly renewed. The aim of this study was to analyse the changes in prescribing patterns of antidiabetic drugs for treating patients with T2DM in Hungary between 2015 and 2020. Material and Methods: In this retrospective, nationwide analysis, we used the central database of the National Health Insurance Fund. We present annual numbers and their proportion of T2DM patients with different treatment regimens. Results: In the period of 2015-2020, the number of incident cases decreased from 60,049 to 29,865, while prevalent cases increased from 682,274 to 752,367. Patients with metformin (MET) monotherapy had the highest prevalence (31% in 2020). Prevalence of insulin (INS) monotherapy continuously but slightly decreased from 29% to 27% while that of sulfonylurea (SU) monotherapy markedly decreased from 37% to 20%. Dipeptidyl peptidase (DPP-4) inhibitors remained popular in 2020 as monotherapy (5%), in dual combination with MET (12%) and in triple combination with MET and SU (5%). The prevalence of patients with sodium-glucose co-transporter-2 (SGLT-2) inhibitors increased from 1% to 4% in monotherapy, from <1% to 6% in dual combination with MET, and from <1% to 2% in triple oral combination with MET and SU or DPP-4-inhibitors. The prevalence of patients using glucagon-like peptide-1 receptor agonists (GLP-1-RAs) also increased but remained around 1-2% both in monotherapy and combinations. For initiating antihyperglycaemic treatment, MET monotherapy was the most frequently used regime in 2020 (50%), followed by monotherapy with SUs (16%) or INS (10%). After initial MET monotherapy, the incidence rates of patients with add-on GLP-1-RAs (2%, 3%, and 4%) and those of add-on SGLT-2 inhibitors (4%, 6%, and 8%) slowly increased in the subsequent 24, 48, and 72 months, respectively. Conclusions: In the period of 2015-2020, we documented important changes in trends of antihyperglycaemic therapeutic patterns in patients with T2DM which followed the new scientific recommendations but remained below our expectations regarding timing and magnitude. More efforts are warranted to implement new agents with cardiovascular/renal benefits into therapeutic management in time, in a much larger proportion of T2DM population, and without delay.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Humanos , Hipoglicemiantes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Estudos Retrospectivos , Hungria/epidemiologia , Glicemia , Compostos de Sulfonilureia/uso terapêutico , Metformina/uso terapêutico , Insulina/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Simportadores/uso terapêutico , Sódio
20.
Nutrients ; 14(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36296965

RESUMO

The current bibliometric review evaluated recent papers that researched dietary protein sources to generate antidiabetic bioactive peptides/hydrolysates for the management of diabetes. Scopus and PubMed databases were searched to extract bibliometric data and, after a systematic four-step process was performed to select the articles, 75 papers were included in this review. The countries of origin of the authors who published the most were China (67%); Ireland (59%); and Spain (37%). The journals that published most articles on the subject were Food Chemistry (n = 12); Food & Function (n = 8); and Food Research International (n = 6). The most used keywords were 'bioactive peptides' (occurrence 28) and 'antidiabetic' (occurrence 10). The most used enzymes were Alcalase® (17%), Trypsin (17%), Pepsin, and Flavourzyme® (15% each). It was found that different sources of protein have been used to generate dipeptidyl peptidase IV (DPP-IV), α-amylase, and α-glucosidase inhibitory peptides. In addition to antidiabetic properties, some articles (n = 30) carried out studies on multifunctional bioactive peptides, and the most cited were reported to have antioxidant and antihypertensive activities (n = 19 and 17, respectively). The present review intended to offer bibliometric data on the most recent research on the production of antidiabetic peptides from dietary proteins to those interested in their obtention to act as hypoglycemic functional ingredients. The studies available in this period, compiled, are not yet enough to point out the best strategies for the production of antidiabetic peptides from food proteins and a more systematic effort in this direction is necessary to allow a future scale-up for the production of these possible functional ingredients.


Assuntos
Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Dipeptidil Peptidase 4/metabolismo , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , alfa-Glucosidases , Pepsina A , Antioxidantes , Tripsina , Anti-Hipertensivos , Peptídeos/farmacologia , alfa-Amilases , Subtilisinas , Proteínas na Dieta , Bibliometria
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