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1.
BMJ ; 367: l5887, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690574

RESUMO

Diabetes is a major and costly health concern worldwide, with high morbidity, disability, mortality, and impaired quality of life. The vast majority of people living with diabetes have type 2 diabetes. Historically, the main strategy to reduce complications of type 2 diabetes has been intensive glycemic control. However, the body of evidence shows no meaningful benefit of intensive (compared with moderate) glycemic control for microvascular and macrovascular outcomes important to patients, with the exception of reduced rates of non-fatal myocardial infarction. Intensive glycemic control does, however, increase the risk of severe hypoglycemia and incurs additional burden by way of polypharmacy, side effects, and cost. Additionally, data from cardiovascular outcomes trials showed that cardiovascular, kidney, and mortality outcomes may be improved with use of specific classes of glucose lowering drugs largely independently of their glycemic effects. Therefore, delivering evidence based, patient centered care to people with type 2 diabetes requires a paradigm shift and departure from the predominantly glucocentric view of diabetes management. Instead of prioritizing intensive glycemic control, the focus needs to be on ensuring access to adequate diabetes care, aligning glycemic targets to patients' goals and situations, minimizing short term and long term complications, reducing the burden of treatment, and improving quality of life.


Assuntos
Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Qualidade de Vida , Glicemia/análise , Glicemia/efeitos dos fármacos , Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/normas , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Incidência , Metanálise como Assunto , Assistência Centrada no Paciente/métodos , Assistência Centrada no Paciente/normas , Guias de Prática Clínica como Assunto , Revisão Sistemática como Assunto , Resultado do Tratamento
2.
N Engl J Med ; 381(18): 1707-1717, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31618560

RESUMO

BACKGROUND: Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes. METHODS: In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring. RESULTS: A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P<0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was >180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was <70 mg per deciliter or <54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P<0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P = 0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Pâncreas Artificial , Adolescente , Adulto , Idoso , Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Desenho de Equipamento , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Sistemas de Infusão de Insulina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pâncreas Artificial/efeitos adversos , Adulto Jovem
3.
Medicina (B Aires) ; 79(4): 241-250, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31487242

RESUMO

Type 2 diabetes is a chronic, progressive disease with increasing prevalence and still late diagnostic. This leads to an increase in the incidence of chronic complications, with signifi cantly increasing health costs. There is also a delay in the onset of insulin therapy in patients with type 2 diabetes for causes related to both patients and physicians. Despite advances in treatment, a low proportion of patients achieve adequate glycemic control. The high hypoglycemia prevalence, consequence of insulin, has led to the development of a new generation long-acting basal insulins to achieve a more stable and prolonged action profile, reducing the variability and risk of hypoglycemia. The EDITION program evaluated the efficacy and safety of glargine U300 compared to glargine U100 in patients with type 1 and 2 diabetes at different stages of the disease. Gla-300 is a new formulation of insulin glargine which has a more stable and prolonged pharmacokinetic and pharmacodynamic profile. Gla-300 demonstrated efficacy and tolerability comparable to glargine U100, with a significant decrease in the risk of hypoglycemia, at night and in 24 hours, providing greater flexibility in the injection schedule, with a window of 6 hours. No increase in weight was observed compared to glargine U100. Bright study (2018) compared glargine U300 vs. degludec U100, demonstrating greater benefit in relation to the risk of hypoglycemia with Gla-300 during titration period. Gla-300 is a last-generation basal insulin, available to improve metabolic control, with a lower risk of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina Glargina/administração & dosagem , Insulina Glargina/farmacocinética , Medicina Baseada em Evidências , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Insulina Glargina/efeitos adversos
4.
Lancet ; 394(10208): 1519-1529, 2019 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-31542292

RESUMO

BACKGROUND: Early treatment intensification leading to sustained good glycaemic control is essential to delay diabetic complications. Although initial combination therapy has been suggested to offer more opportunities than a traditional stepwise approach, its validity remains to be determined. METHODS: Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) was a randomised, double-blind, parallel-group study of newly diagnosed patients with type 2 diabetes conducted in 254 centres across 34 countries. The study consisted of a 2-week screening visit, a 3-week metformin-alone run-in period, and a 5-year treatment period, which was further split into study periods 1, 2, and 3. Patients aged 18-70 years were included if they had type 2 diabetes diagnosed within 2 years prior to enrolment, and centrally confirmed glycated haemoglobin A1c (HbA1c) of 48-58 mmol/mol (6·5-7·5%) and a body-mass index of 22-40 kg/m2. Patients were randomly assigned in a 1:1 ratio either to the early combination treatment group or to the initial metformin monotherapy group, with the help of an interactive response technology system and simple randomisation without stratification. Patients, investigators, clinical staff performing the assessments, and data analysts were masked to treatment allocation. In study period 1, patients received either the early combination treatment with metformin (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and vildagliptin 50 mg twice daily, or standard-of-care initial metformin monotherapy (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and placebo twice daily. If the initial treatment did not maintain HbA1c below 53 mmol/mol (7·0%), confirmed at two consecutive scheduled visits which were 13 weeks apart, patients in the metformin monotherapy group received vildagliptin 50 mg twice daily in place of the placebo and entered study period 2, during which all patients received the combination therapy. The primary efficacy endpoint was the time from randomisation to initial treatment failure, defined as HbA1c measurement of at least 53 mmol/mol (7·0%) at two consecutive scheduled visits, 13 weeks apart from randomisation through period 1. The full analysis set included patients who received at least one randomised study medication and had at least one post-randomisation efficacy parameter assessed. The safety analysis set included all patients who received at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, NCT01528254. FINDINGS: Trial enrolment began on March 30, 2012, and was completed on April 10, 2014. Of the 4524 participants screened, 2001 eligible participants were randomly assigned to either the early combination treatment group (n=998) or the initial metformin monotherapy group (n=1003). A total of 1598 (79·9%) patients completed the 5-year study: 811 (81·3%) in the early combination therapy group and 787 (78·5%) in the monotherapy group. The incidence of initial treatment failure during period 1 was 429 (43·6%) patients in the combination treatment group and 614 (62·1%) patients in the monotherapy group. The median observed time to treatment failure in the monotherapy group was 36·1 (IQR 15·3-not reached [NR]) months, while the median time to treatment failure time for those receiving early combination therapy could only be estimated to be beyond the study duration at 61·9 (29·9-NR) months. A significant reduction in the relative risk for time to initial treatment failure was observed in the early combination treatment group compared with the monotherapy group over the 5-year study duration (hazard ratio 0·51 [95% CI 0·45-0·58]; p<0·0001). Both treatment approaches were safe and well tolerated, with no unexpected or new safety findings, and no deaths related to study treatment. INTERPRETATION: Early intervention with a combination therapy of vildagliptin plus metformin provides greater and durable long-term benefits compared with the current standard-of-care initial metformin monotherapy for patients with newly diagnosed type 2 diabetes. FUNDING: Novartis.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Vildagliptina/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento , Vildagliptina/efeitos adversos
6.
Expert Opin Investig Drugs ; 28(9): 741-747, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31398075

RESUMO

Introduction: Type 2 diabetes is a complex metabolic disorder defined by hyperglycemia which occurs because of impaired insulin secretion and sensitivity. There is an ongoing need to develop novel therapies that are effective and safe with minimal side effects and long-term durability. TTP399 is a hepatoselective, glucokinase activator with potential for treating type 2 diabetes. Areas covered: This is a review of the available data regarding the mechanism of action and the pharmacokinetics of TTP399. The efficacy and safety of the drug for treatment of type 2 diabetes will also be examined with an emphasis on the results of a randomized, controlled phase 2 study. Expert opinion: TTP399 could offer significant advantages over currently available therapies for type 2 diabetes. It successfully lowers glucose without side effects such as hypoglycemia, weight gain or dyslipidemia. Larger trials are required to understand long-term efficacy and safety of this medication in various patient populations and to elucidate its effect on the pathologic processes underpinning type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/fisiopatologia , Glucoquinase/efeitos dos fármacos , Glucoquinase/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Fígado/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
BMJ ; 366: l4894, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462492

RESUMO

OBJECTIVE: To evaluate if the lowest target level for glycated haemoglobin (HbA1c) of <6.5% is associated with lower risk for retinopathy and nephropathy than less tight control in children and adults with type 1 diabetes. DESIGN: Population based cohort study. SETTING: Swedish National Diabetes Registry, 1 January 1998 to 31 December 2017. PARTICIPANTS: 10 398 children and adults with type 1 diabetes followed from diagnosis, or close thereafter, until end of 2017. MAIN OUTCOME MEASURES: Relative risk (odds ratios) for retinopathy and nephropathy for different mean levels of HbA1c. RESULTS: Mean age of participants was 14.7 years (43.4% female), mean duration of diabetes was 1.3 years, and mean HbA1c level was 8.0% (63.4 mmol/mol). After adjustment for age, sex, duration of diabetes, blood pressure, blood lipid levels, body mass index, and smoking, the odds ratio for mean HbA1c <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol) for any retinopathy (simplex or worse) was 0.77 (95% confidence interval 0.56 to 1.05, P=0.10), for preproliferative diabetic retinopathy or worse was 3.29 (0.99 to 10.96, P=0.05), for proliferative diabetic retinopathy was 2.48 (0.71 to 8.62, P=0.15), for microalbuminuria or worse was 0.98 (0.60 to 1.61, P=0.95), and for macroalbuminuria was 2.47 (0.69 to 8.87, P=0.17). Compared with HbA1c levels 6.5-6.9%, HbA1c levels 7.0-7.4% (53-57 mmol/mol) were associated with an increased risk of any retinopathy (1.31, 1.05 to 1.64, P=0.02) and microalbuminuria (1.55, 1.03 to 2.32, P=0.03). The risk for proliferative retinopathy (5.98, 2.10 to 17.06, P<0.001) and macroalbuminuria (3.43, 1.14 to 10.26, P=0.03) increased at HbA1c levels >8.6% (>70 mmol/mol). The risk for severe hypoglycaemia was increased at mean HbA1c <6.5% compared with 6.5-6.9% (relative risk 1.34, 95% confidence interval 1.09 to 1.64, P=0.005). CONCLUSIONS: Risk of retinopathy and nephropathy did not differ at HbA1c levels <6.5% but increased for severe hypoglycaemia compared with HbA1c levels 6.5-6.9%. The risk for severe complications mainly occurred at HbA1c levels >8.6%, but for milder complications was increased at HbA1c levels >7.0%.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/epidemiologia , Retinopatia Diabética/epidemiologia , Hemoglobina A Glicada/análise , Hipoglicemia/complicações , Adolescente , Adulto , Glicemia/análise , Glicemia/efeitos dos fármacos , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Retinopatia Diabética/sangue , Retinopatia Diabética/etiologia , Feminino , Seguimentos , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Suécia/epidemiologia , Adulto Jovem
8.
Expert Opin Investig Drugs ; 28(9): 811-820, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402716

RESUMO

Introduction: More than 424 million adults have diabetes mellitus (DM). This number is expected to increase to 626 million by 2045. The majority (90-95%) of people with DM has type 2-diabetes (T2DM). The continued prevalence of DM and associated complications has prompted investigators to find new therapies. One of the most recent additions to the anti-diabetic armamentarium are inhibitors of sodium-glucose co-transporters 1 and 2 (SGLT1, SGLT2). Areas covered: The authors review the status of SGLT2 inhibitors for the treatment of T2DM and place an emphasis on those agents in early phase clinical trials. Data and information were retrieved from American Diabetes Association, Diabetes UK, ClinicalTrials.gov, PubMed, and Scopus websites. The keywords used in the search were T2DM, SGLT1, SGLT2, and clinical trials. Expert opinion: The benefits of SGLT inhibitors include reductions in serum glycated hemoglobin (HbA1c), body weight, blood pressure and cardiovascular and renal events. However, SGLT inhibitors increase the risk of genitourinary tract infections, diabetic ketoacidosis, and bone fractures. The development of SGLT inhibitors with fewer side effects and as combination therapies are the key to maximizing the therapeutic effects of this important class of anti-diabetic drug.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Adulto , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
9.
Orv Hetil ; 160(34): 1346-1352, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31423831

RESUMO

Introduction: Some meta-analyses suggested a positive effect of metformin therapy on lipid parameters, but the potential beneficial effect of metformin on cardiovascular risk in type 2 diabetes is not entirely clear. Aim: We investigated the effect of metformin therapy on lipid parameters and cardiovascular risk in patients with type 2 diabetes. Method: In a cross-sectional, monocentric study, 102 patients with type 2 diabetes without lipid-lowering medication were analysed for lipid profile and cardiovascular risk (United Kingdom Prospective Diabetes Study Risk Calculator) depending on metformin therapy. The patients were divided into two subgroups regarding with (n = 52) or without metformin therapy (n = 50). Results: Patients with metformin therapy had significantly lower total cholesterol and LDL cholesterol levels than patients without metformin (p<0.01 and p<0.05). This effect was independent from glucose control. No intrinsic effect of metformin could be found on systolic blood pressure, HDL cholesterol, triglycerides, and long-term cardiovascular risk using a multivariable risk assessment score. Conclusion: Metformin therapy has beneficial effects on cholesterol levels without improving cardiovascular risk in patients with type 2 diabetes. Orv Hetil. 2019; 160(34): 1346-1352.


Assuntos
Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , HDL-Colesterol/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Lipídeos/sangue , Metformina/uso terapêutico , Estudos Prospectivos , Fatores de Risco , Reino Unido
10.
Medicine (Baltimore) ; 98(30): e16575, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348290

RESUMO

BACKGROUND: Dapagliflozin, a novel inhibitor of sodium-glucose cotransporter-2 (SGLT-2), lowers blood glucose level by specifically inhibiting the activity of SGLT-2. Previous studies showed efficacy and safety of dapagliflozin combined with other antihyperglycemic agents in type 2 diabetes (T2DM), however, there are few studies for dapagliflozin as monotherapy. The aim of this study was to assess the efficacy and safety of dapagliflozin as a monotherapy in T2DM and provide theoretical basis for clinical rational use of drugs. METHODS: We did a systematic review and meta-analysis of randomized, placbo-controlled clinical studies in patients with type 2 diabetes. We searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP database through October 2018, we also manually screened list of references to the previous meta-analysis of dapagliflozin in the treatment of type 2 diabetes. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. A meta-analysis was conducted by using RevMan 5.3 software. RESULTS: Six randomized controlled trials (RCTs) including 2033 patients were analyzed. Compared with placebo, dapagliflozin monotherapy was associated with a reduction in glycosylated hemoglobin A1c (HbA1c) (weighted mean difference [WMD]: -0.60%; 95% confidence interval [CI]: -0.67%, -0.52%; P < .00001), fasting plasam glucose (FPG) (WMD: -1.30 mmol/L; 95% CI: -1.52, -1.08; P < .00001), and body weight (WMD: -1.50 kg; 95% CI: -1.67, -1.32; P < .00001). Dapagliflozin was associated with an increased risk of urinary tract infections (relative risk [RR]: 1.74; 95% CI: 1.21, 2.49; P = .003) and genital tract infections (RR: 3.52; 95% CI: 2.06, 6.03; P < .00001). CONCLUSIONS: Dapagliflozin monotherapy was well tolerated and effective in reducing the level of HbA1c, FPG, and body weight in patients with T2DM without increasing hypoglycaemia, although it may increase the risk of urinary tract infections and genital tract infections. This meta-analysis provides an evidence for the treatment in patients with T2DM. However, more randomized clinical evidences are still needed to verify the results.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
11.
JAMA ; 322(4): 326-335, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31334795

RESUMO

Importance: Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. Objectives: To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. Design, Setting, and Participants: The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ≥150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Interventions: Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n = 581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n = 570) for up to 72 hours. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Results: Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P = .55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Conclusions and Relevance: Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT01369069.


Assuntos
Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Acidente Vascular Cerebral/complicações , Idoso , Isquemia Encefálica/complicações , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Hiperglicemia/complicações , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Infusões Intravenosas , Injeções Subcutâneas , Insulina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
12.
Expert Opin Pharmacother ; 20(14): 1679-1687, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31335214

RESUMO

Introduction: A growth in the market for anti-diabetic drugs, along with an ever-increasing population suffering from type 2 diabetes mellitus (T2DM), requires a critical re-evaluation of anti-diabetic drugs used for a long time, in order to provide up-to-date practical prescribing information for clinicians. Alogliptin benzoate was firstly approved in 2010 in Japan for T2DM, both as a monotherapy or in combination with other anti-diabetic drugs. Areas covered: This article provides a comprehensive review of the latest data on alogliptin benzoate, including hypoglycemic activity and safety. Expert opinion: The cumulative evidence for alogliptin benzoate is robust with regards to glycemic efficacy and safety. Low hypoglycemia risks and weight changes support its consideration as a first-line medication for T2DM, either as a monotherapy or in combination therapy with other anti-diabetic drugs such as metformin. Ongoing trials will look to better analyze and address its safety and efficacy in pediatric patients and expand our clinical knowledge of this medication.


Assuntos
Benzoatos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Meia-Vida , Humanos , Hipoglicemia/patologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Uracila/efeitos adversos , Uracila/farmacocinética , Uracila/uso terapêutico
13.
Kardiologiia ; 59(7): 76-83, 2019 Jul 19.
Artigo em Russo | MEDLINE | ID: mdl-31322093

RESUMO

In 2008 the Food and Drug Administration has revised approval process for new antidiabetic agents and introduced a requirement to demonstrate the cardiovascular safety in an international multicenter trial. Currently cardiovascular outcome trials of dipeptidyl peptidase-4 (DPP-4) inhibitors (SAVOR-TIMI53, EXAMINE and TECOS), sodium-glucose cotransporter 2 inhibitors (EMPAREG, CANVAS), glucagon-like peptide-1 receptor agonists (ELIXA, EXSCEL LEADER and SUSTAIN-6), ultralong-acting and insulin (DEVOTE) have been completed. The trials confirmed cardiovascular safety of these glucose-lowering medications, and in addition, EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin) and LEADER (liraglutide) have also demonstrated cardioprotective effect of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. These data led to the changes of clinical guidelines for the management of type 2 diabetes.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipoglicemiantes/efeitos adversos , Cardiotoxicidade , Doenças Cardiovasculares/induzido quimicamente , Glucose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose
14.
Diabetes Res Clin Pract ; 154: 75-81, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31271810

RESUMO

AIMS: To evaluate the impact of a prepregnancy care (PPC) programme, beyond HbA1c, on hypoglycaemia awareness and glycaemic variability (GV). METHODS: Prospective pilot study. We selected women with Type 1 diabetes who initiated a PPC programme with normal hypoglycaemia awareness (n = 24). Hypoglycaemia awareness, hypoglycaemic events and GV derived from masked-continuous glucose monitoring were evaluated in the first visit and within 2 weeks after pregnancy confirmation. RESULTS: The duration was 16.5 ±â€¯13.0 months. HbA1c significantly decreased (-0.8 ±â€¯0.7; p < 0.001). The Clarke score increased (0[0-1] vs. 1[0-2] points, p = 0.164), 2 out of 24 were reclassified as having impaired awareness of hypoglycaemia and 2 presented severe hypoglycaemia. GV decreased: standard deviation (p = 0.008), coefficient of variation (p = 0.021), mean amplitude of glycaemic excursions (p = 0.007), average daily risk range (p < 0.001), J-index (p = 0.010), high blood glucose index (HBGI) (p = 0.004), continuous overall net glycaemic action (CONGA) (p = 0.018), mean of daily differences (p = 0.045) and glycaemic risk assessment diabetes equation (p = 0.012). Final HbA1c was associated with baseline J-index, CONGA and HBGI (ß = 0.535, ß = 0.466, ß = 0.534, respectively; p < 0.05). CONCLUSIONS: A PPC programme improved HbA1c as well as GV with no significant impact on hypoglycaemia awareness. Moreover, GV could help to identify women less likely to achieve glycaemic targets. Larger studies are needed to confirm these results.


Assuntos
Automonitorização da Glicemia/normas , Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Conhecimentos, Atitudes e Prática em Saúde , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Cuidado Pré-Concepcional/métodos , Adulto , Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Hemoglobina A Glicada/análise , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hiperglicemia/diagnóstico , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemia/diagnóstico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Projetos Piloto , Prognóstico , Estudos Prospectivos
15.
High Blood Press Cardiovasc Prev ; 26(4): 345-350, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31352663

RESUMO

INTRODUCION: Treatment strategies for patients with pre-hypertension and low-moderate cardiovascular (CV) risk may include nutraceutical compounds (NCs). AIM: To investigate the efficacy and safety of a new-generation of NC in lowering BP values and improving metabolic profile, in a group of hyper-cholesterolemic subjects with pre-hypertension. METHODS: 131 subjects with pre-hypertension (systolic BP 130-139 mmHg and/or diastolic BP 85-89 mmHg) without organ damage and history of CV diseases were enrolled. 66 subjects were treated with a once-daily oral formulation of a NC (red yeast rice, Berberine, Coenzyme Q10, folic acid and chrome) added to diet for 3 months, while 65 patients followed a diet only. Differences in serum total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDLC and HDLC), triglycerides (TG), glycemia, creatine phosphokinase (CPK), aspartate aminotransferase (AST) alanine aminotransferase (ALT) and body mass index (BMI) were evaluated. RESULTS: At the end of treatment, significant reductions of TC, LDLC, TG glucose levels were observed in both treatment groups, while HDLC values increased in the active treatment group only. A greater reduction of TC, LDLC and glycemia was observed in the treatment group. TG levels were not different within the two groups. BP and BMI levels remained unchanged, as well AST, ALT; CPK slightly increased in both groups, but it remained in the normal range. CONCLUSIONS: In patients with pre-hypertension, NC supplementation was safe, well tolerated and effective in improving lipid pattern and glucose levels and in preventing the progression to overt hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais , Hipercolesterolemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Pré-Hipertensão/tratamento farmacológico , Idoso , Anti-Hipertensivos/efeitos adversos , Biomarcadores/sangue , Glicemia/metabolismo , Suplementos Nutricionais/efeitos adversos , Progressão da Doença , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Hipoglicemiantes/efeitos adversos , Hipolipemiantes/efeitos adversos , Itália , Masculino , Pessoa de Meia-Idade , Pré-Hipertensão/diagnóstico , Pré-Hipertensão/fisiopatologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
16.
Drugs ; 79(10): 1135-1146, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31236801

RESUMO

Dapagliflozin (Forxiga®) is a highly potent, reversible and selective sodium-glucose cotransporter-2 inhibitor indicated worldwide for the treatment of type 2 diabetes (T2D). In the EU, oral dapagliflozin once daily is approved for use as monotherapy (in patients who are intolerant of metformin) and as add-on combination therapy (with other glucose-lowering agents, including insulin) for T2D when diet and exercise alone do not provide adequate glycaemic control. In numerous well-designed clinical studies and their extensions, dapagliflozin as monotherapy and combination therapy with other antihyperglycaemic agents provided effective glycaemic control and reduced bodyweight and blood pressure (BP) across a broad spectrum of patients. Dapagliflozin reduced the rate of cardiovascular (CV) death or hospitalization for heart failure (HHF), did not adversely affect major adverse CV events (MACE) and possibly reduced progression of renal disease relative to placebo in patients with established atherosclerotic CV disease (CVD) or multiple risk factors for CVD. Dapagliflozin was generally well tolerated, with a low risk of hypoglycaemia; diabetic ketoacidosis (DKA), although rare, and genital infections were more common with dapagliflozin than placebo. Given its antihyperglycaemic, cardioprotective and possibly renoprotective properties and generally favourable tolerability profile, dapagliflozin provides an important option for the management of a broad patient population, regardless of the history of CVD.


Assuntos
Compostos Benzidrílicos/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Aprovação de Drogas , Quimioterapia Combinada/métodos , Europa (Continente) , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Insulina/farmacologia , Gravidez , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
17.
Adv Mater ; 31(30): e1901051, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31165524

RESUMO

Insulin-dependent patients with diabetes mellitus require multiple daily injections of exogenous insulin to combat hyperglycemia. However, administration of excess insulin can lead to hypoglycemia, a life-threatening condition characterized by abnormally low blood glucose levels (BGLs). To prevent hypoglycemia associated with intensive insulin therapy, a "smart" composite microneedle (cMN) patch is developed, which releases native glucagon at low glucose levels. The cMN patch is composed of a photo-crosslinked methacrylated hyaluronic acid (MeHA) microneedle array with embedded multifunctional microgels. The microgels incorporate zwitterionic moieties that stabilize loaded glucagon and phenylboronic acid moieties that provide glucose-dependent volume change to facilitate glucagon release. Hypoglycemia-triggered release of structurally unchanged glucagon from the cMN patch is demonstrated in vitro and in a rat model of type 1 diabetes (T1D). Transdermal application of the patch prevented insulin-induced hypoglycemia in the diabetic rats. This work is the first demonstration of a glucose-responsive glucagon-delivery MN patch for the prevention of hypoglycemia, which has a tremendous potential to reduce the dangers of intensive insulin therapy and improve the quality of life of patients with diabetes and their caregivers.


Assuntos
Glicemia/metabolismo , Glucagon/administração & dosagem , Hipoglicemia/tratamento farmacológico , Agulhas , Animais , Reagentes para Ligações Cruzadas/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Liberação Controlada de Fármacos , Géis , Humanos , Ácido Hialurônico/análogos & derivados , Ácido Hialurônico/química , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Metacrilatos/química , Processos Fotoquímicos , Polimerização , Ratos , Adesivo Transdérmico
18.
N Engl J Med ; 381(9): 841-851, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31185157

RESUMO

BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Administração Oral , Idoso , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , 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 Drogas , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Patentes como Assunto
20.
Drugs ; 79(10): 1157-1161, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31201711

RESUMO

Remogliflozin, a selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor, which is to be administered as remogliflozin etabonate (Remo™, Remozen™), the prodrug for remogliflozin, recently received its first approval as a treatment for type 2 diabetes mellitus (T2DM) in India. This article summarizes the milestones in the development of remogliflozin etabonate leading to this first approval for T2DM.


Assuntos
Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Pirazóis/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2 , Aprovação de Drogas , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Índia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
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