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1.
JAMA ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32219386

RESUMO

Importance: Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. Objective: To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. Design, Setting, and Participants: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%. Results: Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. Conclusions and Relevance: In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.

2.
Eur Heart J ; 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32221582

RESUMO

AIMS: In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether this benefit was consistent in relation to background HF therapy. METHODS AND RESULTS: In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n = 4744) were treated with a diuretic (84%), renin-angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 [95% confidence interval (CI) 0.65-0.85] for the primary composite endpoint (P < 0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61-0.86) compared with 0.77 (95% CI 0.63-0.94) in those not on all three of these treatments (P-interaction 0.64). CONCLUSION: The benefit of dapagliflozin was consistent regardless of background therapy for HF.

3.
Circulation ; 141(2): 100-111, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736328

RESUMO

BACKGROUND: The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly. METHODS: Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min-1·1.73 m-2. The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first. RESULTS: A total of 4744 patients 22 to 94 years of age (mean age, 66.3 [SD 10.9] years) were randomized: 636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4-17.9), 15.7 (95% CI, 13.2-18.7), 15.1 (95% CI, 13.1-17.5), and 18.0 (95% CI, 15.2-21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88; P for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group. CONCLUSIONS: Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

4.
Circulation ; 141(2): 90-99, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736335

RESUMO

BACKGROUND: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium-glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months. RESULTS: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3-91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57-0.86]; hazard ratio, 0.77 [95% CI, 0.61-0.98]; hazard ratio, 0.62 [95% CI, 0.46-0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P<0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78-0.90]; P<0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08-1.23]; odds ratio, 1.15 [95% CI, 1.08-1.22]; odds ratio, 1.14 [95% CI, 1.07-1.22]; number needed to treat=14, 15, and 18, respectively; P<0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score). CONCLUSIONS: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

5.
N Engl J Med ; 381(21): 1995-2008, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31535829

RESUMO

BACKGROUND: In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. METHODS: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. RESULTS: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Compostos Benzidrílicos/efeitos adversos , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/mortalidade , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Feminino , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/análise , Insuficiência Cardíaca/complicações , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico
6.
Eur J Heart Fail ; 21(11): 1402-1411, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31309699

RESUMO

BACKGROUND: The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial, (ii) compare DAPA-HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre-diabetes and a normal glycated haemoglobin (HbA1c) in DAPA-HF. METHODS AND RESULTS: Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N-terminal pro-B-type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA-HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre-diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c < 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre-diabetes and 33% normal HbA1c. Overall, DAPA-HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 96% beta-blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co-morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non-insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%. CONCLUSIONS: Patients randomized in DAPA-HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose-lowering therapy. Consequently, DAPA-HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03036124.

7.
Eur J Heart Fail ; 21(5): 665-675, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30895697

RESUMO

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of incident heart failure hospitalization in individuals with type 2 diabetes who have, or are at high risk of, cardiovascular disease. Most patients in these trials did not have heart failure at baseline and the effect of SGLT2 inhibitors on outcomes in individuals with established heart failure (with or without diabetes) is unknown. DESIGN AND METHODS: The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) is an international, multicentre, parallel group, randomized, double-blind, study in patients with chronic heart failure, evaluating the effect of dapagliflozin 10 mg, compared with placebo, given once daily, in addition to standard care, on the primary composite outcome of a worsening heart failure event (hospitalization or equivalent event, i.e. an urgent heart failure visit) or cardiovascular death. Patients with and without diabetes are eligible and must have a left ventricular ejection fraction ≤ 40%, a moderately elevated N-terminal pro B-type natriuretic peptide level, and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 . The trial is event-driven, with a target of 844 primary outcomes. Secondary outcomes include the composite of total heart failure hospitalizations (including repeat episodes), and cardiovascular death and patient-reported outcomes. A total of 4744 patients have been randomized. CONCLUSIONS: DAPA-HF will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in a broad spectrum of patients with heart failure and reduced ejection fraction.

8.
JAMA Cardiol ; 3(2): 155-163, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29214305

RESUMO

Importance: An elevated level of urinary albumin to creatinine ratio (UACR) is a marker of renal dysfunction and predictor of kidney failure/death in patients with type 2 diabetes. The prognostic use of UACR in established cardiac biomarkers is not well described. Objective: To evaluate whether UACR offers incremental prognostic benefit beyond risk factors and established plasma cardiovascular biomarkers. Design, Setting, and Participants: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 study was performed from May 2010 to May 2013 and evaluated the safety of saxagliptin vs placebo in patients with type 2 diabetes with overt cardiovascular disease or multiple risk factors. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years). Interventions: Patients were randomized to saxagliptin vs placebo plus standard care. Main Outcomes and Measures: Baseline UACR was measured in 15 760 patients (95.6% of the trial population) and categorized into thresholds. Results: Of 15 760 patients, 5205 were female (33.0%). The distribution of UARC categories were: 5805 patients (36.8%) less than 10 mg/g, 3891 patients (24.7%) at 10 to 30 mg/g, 4426 patients (28.1%) at 30 to 300 mg/g, and 1638 patients (10.4%) at more than 300 mg/g. When evaluated without cardiac biomarkers, there was a stepwise increase with each higher UACR category in the incidence of the primary composite end point (cardiovascular death, myocardial infarction, or ischemic stroke) (3.9%, 6.9%, 9.2%, and 14.3%); cardiovascular death (1.4%, 2.6%, 4.1%, and 6.9%); and hospitalization for heart failure (1.5%, 2.5%, 4.0%, and 8.3%) (adjusted P < .001 for trend). The net reclassification improvement at the event rate for each end point was 0.081 (95% CI, 0.025 to 0.161), 0.129 (95% CI, 0.029 to 0.202), and 0.056 (95% CI, -0.005 to 0.141), respectively. The stepwise increased cardiovascular risk associated with a UACR of more than 10 mg/g was also present within each chronic kidney disease category. The UACR was associated with outcomes after including cardiac biomarkers. However, the improvement in discrimination and reclassification was attenuated; net reclassification improvement at the event rate was 0.022 (95% CI, -0.022 to 0.067), -0.008 (-0.034 to 0.053), and 0.043 (-0.030 to 0.052) for the primary end point, cardiovascular death, and hospitalization for heart failure, respectively. Conclusions and Relevance: In patients with type 2 diabetes, UACR was independently associated with increased risk for a spectrum of adverse cardiovascular outcomes. However, the incremental cardiovascular prognostic value of UACR was minimal when evaluated together with contemporary cardiac biomarkers. Trial Registration: clinicaltrials.gov Identifier: NCT01107886.


Assuntos
Albuminúria/diagnóstico , Diabetes Mellitus Tipo 2/urina , Cardiomiopatias Diabéticas/urina , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Biomarcadores/urina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/urina , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/fisiologia , Insuficiência Cardíaca/etiologia , Hospitalização/estatística & dados numéricos , Humanos , Incretinas/uso terapêutico , Masculino , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/urina
9.
Diabetes Ther ; 8(3): 587-599, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28432619

RESUMO

INTRODUCTION: This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens. METHODS: Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164). RESULTS: Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of ß-cell function. CONCLUSION: Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens. FUNDING: AstraZeneca.

10.
Diabetes Care ; 39(8): 1329-37, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27222508

RESUMO

OBJECTIVE: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied. RESULTS: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/administração & dosagem , Dipeptídeos/efeitos adversos , Hipoglicemia/induzido quimicamente , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Idoso , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Seguimentos , Glibureto/administração & dosagem , Glibureto/efeitos adversos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina de Ação Curta/administração & dosagem , Insulina de Ação Curta/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/prevenção & controle , Fatores de Risco , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversos
11.
Diabetes Res Clin Pract ; 105(2): 185-91, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24947443

RESUMO

AIMS: Saxagliptin reduced glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial glucose (PPG) in Asian patients with type 2 diabetes mellitus (T2DM). To understand the physiology of this effect, indices of α- and ß-cell function were measured in a subpopulation of Chinese patients following a noodle mixed-meal tolerance test. METHODS: Data from Chinese patients were pooled from two phase 3, 24-week studies of saxagliptin 5mg/d as monotherapy in drug-naive patients and as add-on to metformin in patients inadequately controlled with metformin alone. The end points for ß- and α-cell function were change from baseline in C-peptide, insulin, and glucagon areas under the curve from 0 to 180 min (AUC0-180), insulinogenic index, and insulin sensitivity from Matsuda index after a mixed meal. Also glycemic variables, HbA1c, FPG, and PPG (AUC0-180), and homeostasis model assessment (HOMA) 2ß were measured. RESULTS: At 24 weeks, greater improvements in adjusted mean change from baseline HbA1c (difference vs placebo [95% CI], -0.33% [-0.50%, -0.17%], [-4 (-5.5, -1.9) mmol/mol], P<0.0001), FPG (-0.41 [-0.78, -0.03] mmol/L, P=0.03), PPG AUC0-180 (-168 [-245, -91.8] mmol min/L, P<0.0001), C-peptide AUC0-180 (19.7 [5.2, 34.2] nmol min/L, P=0.008), insulinogenic index (0.06% [0.02%, 0.09%], P=0.002), and greater suppression of glucagon secretion (glucagon AUC0-180, -322 [-493.6, -150.7] pmol min/L, P=0.0003) were observed with saxagliptin versus placebo. CONCLUSION: In Chinese patients with T2DM, saxagliptin as monotherapy or as add-on to metformin improved glycemic control by modulating α- and ß-cell function.


Assuntos
Adamantano/análogos & derivados , Glicemia/análise , Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucagon/metabolismo , Período Pós-Prandial/efeitos dos fármacos , Adamantano/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Quimioterapia Combinada , Jejum/fisiologia , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade
12.
J Clin Endocrinol Metab ; 98(1): 245-54, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23118430

RESUMO

OBJECTIVE: The objective of the study was to explore the acute in vivo effects of the selective phosphodiesterase-5 inhibitor tadalafil on local microcirculation and regional metabolism in skeletal muscle and adipose tissue (AT). DESIGN, SETTING, AND PARTICIPANTS: We studied eight postmenopausal female patients with type 2 diabetes (T2D) and eight nondiabetic controls (Ctrl) in the postabsorptive state and 180 min after the administration of tadalafil 10 mg. Intramuscular and sc microdialysis were combined with measurements of forearm (FBF) and AT blood flow as well as with arterial and deep venous blood sampling. Muscle capillary recruitment, as ascertained by the permeability surface area product for glucose (PS(glu)), forearm glucose uptake (FGU), interstitial lactate, and glycerol concentrations, was measured. RESULTS: When compared with Ctrl, T2D patients exhibited lower (P = 0.01) PS(glu) but similar FGU and FBF. After tadalafil, PS(glu) (P = 0.01) and muscle interstitial-arterial (I-A) lactate concentration gradient (P < 0.01) increased significantly in both groups, whereas FBF, FGU, and I-A glycerol remained unchanged. In AT, tadalafil did not significantly affect local blood flow, whereas the sc interstitial (I) lactate and I-A lactate concentrations increased (P < 0.01), and the I-A glycerol decreased in both groups. Finally, in multivariate analysis the PS(glu) was a strong and independent predictor of muscle glucose disposal (ß: 0.737 and 0.963, P < 0.05, in Ctrl and T2D, respectively). CONCLUSIONS: Tadalafil emerges as an acutely acting modulator of microvascular recruitment and glucose metabolism in skeletal muscle and adipose tissue. We suggest that selective phosphodiesterase-5 blockade may provide a path forward to new therapeutics in the setting of insulin resistance.


Assuntos
Carbolinas/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Microvasos/efeitos dos fármacos , Neovascularização Patológica/induzido quimicamente , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/induzido quimicamente , Angiopatias Diabéticas/metabolismo , Feminino , Humanos , Microdiálise , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Neovascularização Patológica/complicações , Inibidores da Fosfodiesterase 5/farmacologia , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/fisiologia , Especificidade por Substrato , Tadalafila
13.
J Clin Endocrinol Metab ; 97(9): 3319-25, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22723318

RESUMO

CONTEXT: Glucokinase is expressed in the hypothalamus, but effects of glucokinase activators (GKAs) on counterregulatory responses to hypoglycemia are unknown. OBJECTIVE: Two separate studies assessed the counterregulatory hormone responses to hypoglycemia induced by the GKAs, AZD6370 and AZD1656, compared with insulin infusion. DESIGN AND SETTING: Both studies were randomized, open, two-way crossover studies, conducted in separate clinical research centers. PARTICIPANTS: Both studies involved 12 healthy adult male volunteers. INTERVENTIONS: Each subject received two treatments in randomized order, separated by a washout. In the AZD6370 study, overnight-fasted subjects received either a single oral AZD6370 dose (300 mg) or insulin infusion (0.8 mU/kg · min). In the AZD1656 study, overnight-fasted subjects received either a single oral dose of AZD1656 (80 mg) plus supporting insulin (1 mU/kg · min) or insulin alone (1 mU/kg · min). Insulin was added to support AZD1656 because AZD1656 alone did not produce the desired hypoglycemia. Plasma glucose was lowered during a stepwise hypoglycemic clamp with a glycemic nadir of 2.7 mmol/liter for 30 min. MAIN OUTCOME MEASURES: Epinephrine, norepinephrine, GH, cortisol, and glucagon plasma levels were assessed. RESULTS: No safety issues were raised. AZD6370 and AZD1656 had no effect on counterregulatory responses for norepinephrine, GH, or cortisol, but epinephrine increased slightly with AZD1656. Glucagon responses were reduced by approximately 30% with both GKAs vs. insulin. CONCLUSIONS: These data suggest the central nervous system-mediated counterregulatory response during GKA-induced hypoglycemia was preserved, whereas the glucagon response was attenuated; the latter was possibly mediated by a local pancreatic effect (intraislet hyperinsulinemia) rather than by impairment of the central nervous system-mediated response.


Assuntos
Azetidinas/farmacologia , Benzamidas/farmacologia , Ativadores de Enzimas/farmacologia , Glucoquinase/efeitos dos fármacos , Glucoquinase/metabolismo , Hipoglicemia/metabolismo , Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Sulfonas/farmacologia , Adulto , Índice de Massa Corporal , Peptídeo C/sangue , Estudos Cross-Over , Epinefrina/sangue , Glucagon/sangue , Hormônio do Crescimento Humano/sangue , Humanos , Hidrocortisona/sangue , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Adulto Jovem
14.
Mol Cell Endocrinol ; 297(1-2): 104-11, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18599191

RESUMO

Dysregulated hormonal, metabolic and neural signalling within and between organs can contribute to development of metabolic diseases including type 2 diabetes. Insulin-antagonistic effects of hormones, cytokines and excess metabolic substrates such as glucose and fatty acids may be exerted via common mechanisms involving for example reactive oxygen species (ROS) accumulation and associated inflammatory responses. Visceral adiposity is a central component of the metabolic syndrome and it is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. In the development of insulin resistance, it is likely that intra-abdominal adipose tissue plays a critical role in a complex endocrine and neural network involving several tissues. This review paper focuses on neuroendocrine 'stress' factors that target insulin-responsive tissues, in particular adipose tissue. We propose that there are common pathways by which dysregulation in different endocrine systems may contribute to the development of type 2 diabetes.


Assuntos
Resistência à Insulina , Sistemas Neurossecretores/metabolismo , Animais , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio/fisiopatologia , Glucose/metabolismo , Humanos , Estresse Fisiológico
15.
J Clin Endocrinol Metab ; 93(7): 2764-73, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18460559

RESUMO

CONTEXT: Impairment of insulin-mediated capillary recruitment in skeletal muscle contributes to a hampered glucose uptake in obesity. OBJECTIVE: The objective of this study was to evaluate whether metacholine (MCh), a nitric oxide vasodilator, potentiates muscle capillary recruitment and forearm glucose uptake (FGU) during physiological hyperinsulinemia. DESIGN: The double-forearm technique [i.e. infused vs. control (Ctrl) forearm] was combined with im microdialysis during an oral glucose tolerance test in 15 nondiabetic, obese subjects divided into a group of insulin-resistant (IR) (n = 7) and insulin-sensitive (n = 8) individuals. RESULTS: After the oral glucose tolerance test, forearm blood flow in the Ctrl forearm was unchanged, whereas it increased about 3-fold (P < 0.0001 vs. baseline) in response to MCh. Capillary permeability surface area product for glucose (PS(glu)) (capillary recruitment), FGU, and interstitial insulin concentrations increased significantly over time (P < 0.001) in both forearms. Compared with insulin-sensitive, the IR subjects exhibited lower PS(glu) (P < 0.001) and FGU (P < 0.01) in the Ctrl arm, whereas this difference was insignificant in the MCh arm despite the blunted forearm blood flow increase. Moreover, in IR individuals MCh significantly (P < 0.05) ameliorated the delayed onset of insulin action, i.e. the FGU response to hyperinsulinemia. Finally, we found PS(glu) to be a strong and independent predictor of FGU response (adjusted R(2) 0.72; P < 0.0001). CONCLUSIONS: MCh-induced vasodilation may improve the microvascular and metabolic responses to physiological hyperinsulinemia in obese, IR individuals. Further studies are required to unravel whether stimulation of nitric oxide production in skeletal muscle may represent an attractive therapeutic approach to bypassing cellular resistance to glucose disposal.


Assuntos
Glucose/metabolismo , Resistência à Insulina , Insulina/fisiologia , Cloreto de Metacolina/farmacologia , Músculo Esquelético/irrigação sanguínea , Obesidade/metabolismo , Adulto , Artéria Braquial , Capilares/efeitos dos fármacos , Capilares/fisiologia , Antebraço/irrigação sanguínea , Humanos , Hiperinsulinismo/metabolismo , Ácido Láctico/sangue , Pessoa de Meia-Idade , Óxido Nítrico/fisiologia , Fluxo Sanguíneo Regional , Vasodilatação/efeitos dos fármacos
17.
Diabetes ; 54(1): 152-7, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15616023

RESUMO

Obese subjects exhibit a delay in insulin action and delivery of insulin to muscle interstitial fluid during glucose/insulin infusion. The aim of the present study was to follow the distribution of insulin to skeletal muscle after an oral glucose load in obese subjects. We conducted an oral glucose tolerance test (OGTT) in 10 lean and 10 obese subjects (BMI 23 +/- 0.6 vs. 33 +/- 1.2 kg/m(2); P < 0.001). Insulin measurements in muscle interstitial fluid were combined with forearm arteriovenous catheterization and blood flow measurements. In the obese group, interstitial insulin was significantly (35-55%) lower than plasma insulin (P < 0.05) during the 1st h after the OGTT, whereas in lean subjects, no significant difference was found between interstitial and plasma insulin levels during the same time period. The permeability surface area product for glucose, representing capillary recruitment, increased in the lean group (P < 0.05) but not in the obese group (NS). Obese subjects had a significantly higher plasma insulin level at 90-120 min after oral glucose (398 +/- 57 vs. 224 +/- 37 pmol/l in control subjects; P < 0.05). The significant gradient between plasma insulin and muscle interstitial insulin during the first hour after OGTT suggests a slow delivery of insulin in obese subjects. The hindered transcapillary transport of insulin may be attributable to a defect in insulin-mediated capillary recruitment.


Assuntos
Capilares/fisiologia , Teste de Tolerância a Glucose , Insulina/metabolismo , Músculo Esquelético/fisiologia , Obesidade/fisiopatologia , Adulto , Transporte Biológico , Glicemia/metabolismo , Índice de Massa Corporal , Tamanho Corporal , Capilares/fisiopatologia , Líquido Extracelular/fisiologia , Feminino , Humanos , Insulina/sangue , Cinética , Masculino , Microdiálise , Músculo Esquelético/fisiopatologia , Valores de Referência
18.
J Clin Endocrinol Metab ; 90(2): 1078-82, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15536160

RESUMO

Capillary recruitment in muscles, induced by insulin, has been proposed to be impaired in insulin-resistant states. To elucidate the mechanisms regulating capillary transport of insulin and glucose in type 2 diabetes, we directly calculated the permeability-surface area product (PS) for glucose and insulin in muscle. Intramuscular microdialysis in combination with the forearm model and blood flow measurements was performed in type 2 diabetic male subjects and age- and weight-matched controls during a euglycemic-hyperinsulinemic clamp. During steady-state hyperinsulinemia, arterial plasma glucose was 5.8 +/- 0.1 and 5.9 +/- 0.1 mmol/liter [not significant (NS)] in the obese and type 2 diabetic subjects, respectively. Venous glucose was significantly lower in the obese group compared with the type 2 diabetic subjects, 4.3 +/- 02 vs. 4.9 +/- 0.2 mmol/liter (P < 0.05). Arterial insulin was 1494 +/- 90 and 1458 +/- 132 pmol/liter (NS) in the obese and type 2 diabetic subjects, respectively. The glucose infusion rate during steady-state hyperinsulinemia was 10.8 +/- 0.8 and 7.2 +/- 0.4 mg/kg.min in the obese and diabetic subjects, respectively (P < 0.01). Interstitial-arterial lactate difference was significantly higher in the obese subjects. During steady-state hyperinsulinemia, PS for glucose was significantly higher in the obese subjects (1.1 +/- 0.2 vs. 0.5 +/- 0.1 ml/min.100 g, P < 0.05). Glucose uptake was also significantly higher in the obese subjects (3.0 +/- 0.4 vs. 1.8 +/- 0.3 mumol/min.100 g, P < 0.05). During steady-state hyperinsulinemia, PS for insulin was 0.4 +/- 0.1 and 0.3 +/- 0.1 ml/min.100 g in the obese and diabetic subjects, respectively (NS), and insulin uptake was 258 +/- 54 vs. 168 +/- 24, respectively (NS). When both subject groups were pooled together, a significant correlation was found between PS for glucose and glucose uptake during steady-state hyperinsulinemia. Skeletal muscle blood flow during steady-state hyperinsulinemia was 1.9 +/- 0.2 and 2.3 +/- 0.4 ml/100 g.min in the obese and diabetic subjects, respectively (NS). Blood flow did not increase during hyperinsulinemia in either of the two groups. The present data clearly show that PS for glucose is subnormal during steady-state hyperinsulinemia in insulin-resistant type 2 diabetic subjects. Furthermore, there was a close correlation between glucose uptake and PS for glucose but not between blood flow and PS. We suggest that PS is a more sensitive marker for insulin resistance during hyperinsulinemia than limb flow. The lower capacity for transcapillary passage found in the type 2 diabetic subjects is suggested to further aggravate insulin resistance.


Assuntos
Capilares/fisiopatologia , Permeabilidade da Membrana Celular/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Glicemia/metabolismo , Índice de Massa Corporal , Jejum , Humanos , Insulina/sangue , Pessoa de Meia-Idade , Valores de Referência
19.
J Clin Endocrinol Metab ; 88(10): 4559-64, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14557422

RESUMO

To elucidate mechanisms regulating capillary transport of insulin and glucose, we directly calculated the permeability surface (PS) area product for glucose and insulin in muscle. Intramuscular microdialysis in combination with the forearm model and blood flow measurements was performed in healthy males, studied during an oral glucose tolerance test or during a one-step or two-step euglycemic hyperinsulinemic clamp. PS for glucose increased significantly from 0.29 +/- 0.1 to 0.64 +/- 0.2 ml/min.100 g after oral glucose tolerance test, and glucose uptake increased from 1.2 +/- 0.4 to 2.6 +/- 0.6 micro mol/min.100 g (P < 0.05). During one-step hyperinsulinemic clamp (plasma insulin, 1.962 pmol/liter), PS for glucose increased from 0.2 +/- 0.1 to 2.3 +/- 0.9 ml/min.100 g (P < 0.05), and glucose uptake increased from 0.6 +/- 0.2 to 5.0 +/- 1.4 micro mol/min.100 g (P < 0.05). During the two-step clamp (plasma insulin, 1380 +/- 408 and 3846 +/- 348 pmol/liter), the arterial-interstitial difference and PS for insulin were constant. The PS for glucose tended to increase (P = not significant), whereas skeletal muscle blood flow increased from 4.4 +/- 0.7 to 6.2 +/- 0.8 ml/min.100 ml (P < 0.05). The present data show that PS for glucose is markedly increased by oral glucose, whereas a further vasodilation exerted by high insulin concentrations may not be physiologically relevant for capillary delivery of either glucose or insulin in resting muscle.


Assuntos
Glucose/farmacocinética , Insulina/metabolismo , Músculo Esquelético/metabolismo , Fluxo Sanguíneo Regional/fisiologia , Adulto , Superfície Corporal , Capilares/metabolismo , Antebraço/irrigação sanguínea , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/metabolismo , Masculino , Microdiálise , Músculo Esquelético/irrigação sanguínea , Vasodilatação/fisiologia
20.
Diabetes ; 51(9): 2742-8, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12196467

RESUMO

Insulin-resistant subjects have a slow onset of insulin action, and the underlying mechanism has not been determined. To evaluate whether a delayed transcapillary transport is part of the peripheral insulin resistance, we followed the kinetics of infused insulin and inulin in plasma and muscle interstitial fluid in obese insulin-resistant patients and control subjects. A total of 10 lean and 10 obese men (BMI 24 +/- 0.8 vs. 32 +/- 0.8 kg/m(2), P < 0.001) was evaluated during a hyperinsulinemic-euglycemic clamp (insulin infusion rate 120 mU. m(-2). min(-1)) combined with an inulin infusion. Measurements of insulin and inulin in plasma were taken by means of arterial-venous catheterization of the forearm and microdialysis in brachioradialis muscle combined with forearm blood flow measurements with vein occlusion pletysmography. The obese subjects had a significantly lower steady-state glucose infusion rate and, moreover, demonstrated a delayed appearance of insulin (time to achieve half-maximal concentration [T(1/2)] 72 +/- 6 vs. 46 +/- 6 min in control subjects, P < 0.05) as well as inulin (T(1/2) 83 +/- 3 vs. 53 +/- 7 min, P < 0.01) in the interstitial fluid. Also, the obese subjects had a delayed onset of insulin action (T(1/2) 70 +/- 9 vs. 45 +/- 5 min in control subjects, P < 0.05), and their forearm blood flow rate was significantly lower. These results demonstrate a delayed transcapillary transport of insulin and inulin from plasma to the muscle interstitial fluid and a delayed onset of insulin action in insulin-resistant obese subjects.


Assuntos
Espaço Extracelular/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Adulto , Glicemia/análise , Capilares , Antebraço/irrigação sanguínea , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Resistência à Insulina/fisiologia , Inulina/sangue , Masculino , Obesidade/fisiopatologia , Valores de Referência , Fluxo Sanguíneo Regional , Magreza
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