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1.
Circulation ; 140(17): 1426-1436, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31634011

RESUMO

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31608926

RESUMO

CONTEXT: Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 (GLP-1) and glucagon activity. OBJECTIVE: To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects. DESIGN/SETTING: Randomized, double-blind, phase 2a study conducted in two cohorts at five clinical trial sites. PATIENTS: 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs. INTERVENTION: Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2). MAIN OUTCOME MEASURES: Coprimary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose AUC0-4h post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2). RESULTS: Patients received cotadutide (cohort 1, n=26; cohort 2, n=20) or placebo (cohort 1, n=13; cohort 2, n=6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0-4h post MMTT (LS mean [90% CI]: -21.52% [-25.68, -17.37] vs 6.32% [0.45, 12.20]; P<0.001) and body weight (-3.41% [-4.37, -2.44] vs -0.08% [-1.45, 1.28]; P=0.002). A significant increase in insulin AUC0-4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P=0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs -42.9 minutes; P=0.0392). CONCLUSION: These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.

3.
Am J Cardiol ; 123(1): 145-152, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30366601

RESUMO

We sought to assess the prevalence of polyvascular disease in patients with type 2 diabetes mellitus (T2DM) and its impact on ischemic events. Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53, a large contemporary, randomized trial, evaluated the effect of saxagliptin versus placebo in 16,492 patients with T2DM and a history of or at risk for cardiovascular (CV) events. Polyvascular disease was defined as a history of clinical events involving 2 or more vascular beds (coronary, peripheral, or cerebrovascular system) at the time of randomization. The primary composite endpoint of CV death, myocardial infarction, or ischemic stroke was compared according to the number of diseased arterial beds. At the time of randomization, 3,667 (22.2%) patients had risk factors for CV events; 11,423 (69.3%) had established 1 arterial bed disease; 1,298 (7.9%) had 2 bed disease; and 104 (0.6%) had 3 bed disease. Compared with diabetic patients with no established atherosclerosis, the adjusted hazard ratio for the composite primary end point in 1, 2, or 3 diseased beds was 1.95, 3.54, and 4.64, respectively (trend p < 0.0001). The adjusted risk for overall mortality increased in a similar stepwise fashion from 1.47 to 2.33 to 3.12, respectively (trend p = 0.0001) with each additional diseased arterial territory. In conclusion, in patients with confirmed atherosclerosis enrolled in SAVOR-TIMI 53, 11% had polyvascular disease; and compared with diabetic patients with single bed disease, the risk of ischemic events and overall mortality was substantially higher in patients with T2DM and polyvascular disease.


Assuntos
Adamantano/análogos & derivados , Transtornos Cerebrovasculares/epidemiologia , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Doenças Vasculares Periféricas/epidemiologia , Adamantano/uso terapêutico , Idoso , Transtornos Cerebrovasculares/mortalidade , Doença das Coronárias/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/mortalidade , Prevalência , Fatores de Risco , Resultado do Tratamento
4.
Diabetologia ; 62(3): 373-386, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30593607

RESUMO

AIMS/HYPOTHESIS: Cardiovascular disease is the leading cause of morbidity and mortality in people with type 2 diabetes. MEDI4166 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and glucagon-like peptide-1 (GLP-1) analogue fusion molecule designed to treat patients with type 2 diabetes who are at risk for cardiovascular disease. In this completed, first-in-human study, we evaluated the safety and efficacy of single or multiple doses of MEDI4166 in participants with type 2 diabetes. METHODS: In this phase 1 study that was conducted across 11 clinics in the USA, eligible adults had type 2 diabetes, a BMI of ≥25 kg/m2 to ≤42 kg/m2, and LDL-cholesterol levels ≥1.81 mmol/l. Participants were randomised 3:1 to receive MEDI4166 or placebo using an interactive voice/web response system, which blinded all participants, investigators and study site personnel to the study drug administered. In 'Part A' of the study, five cohorts of participants received a single s.c. injection of MEDI4166 at 10 mg, 30 mg, 100 mg, 200 mg or 400 mg, or placebo. 'Part B' of the study consisted of three cohorts of participants who received an s.c. dose of MEDI4166 once weekly for 5 weeks at 50 mg, 200 mg or 400 mg, or placebo. The primary endpoint in Part A was safety. The co-primary endpoints in Part B were change in LDL-cholesterol levels and area under the plasma glucose concentration-time curve (AUC0-4h) post-mixed-meal tolerance test (MMTT) from baseline to day 36. The pharmacokinetics and immunogenicity of MEDI4166 were also evaluated. RESULTS: MEDI4166 or placebo was administered to n = 30 or n = 10 participants, respectively, in Part A of the study, and n = 48 or n = 15 participants, respectively, in Part B. The incidence of treatment-emergent adverse events (TEAEs) were comparable between MEDI4166 and placebo in both Part A (60% vs 50%) and Part B (79% vs 87%) of the study. Common TEAEs with MEDI4166 included injection-site reactions, diarrhoea and headache; there was no evidence for dose-related increases in TEAEs. In Part B of the study, at all tested doses of MEDI4166, there was a significant decrease in LDL-cholesterol levels vs placebo (least squares mean [95% CI]; MEDI4166 50 mg, -1.25 [-1.66, -0.84]; MEDI4166 200 mg, -1.97 [-2.26, -1.68]; MEDI4166 400 mg, -1.96 [-2.23, -1.70]; placebo, -0.03 [-0.35, 0.28]; all p < 0.0001). However, there were no clinically relevant reductions or significant differences between MEDI4166 vs placebo in glucose AUC0-4h post-MMTT (least squares mean [95% CI]; MEDI4166 50 mg, -10.86 [-17.69, -4.02]; MEDI4166 200 mg, -4.23 [-8.73, 0.28]; MEDI4166 400 mg, -2.59 [-7.14, 1.95]; placebo, -4.84 [-9.95, 0.28]; all p > 0.05). MEDI4166 was associated with a pharmacokinetic profile supportive of weekly dosing and an overall treatment-induced anti-drug antibody-positive rate of 22%. CONCLUSIONS/INTERPRETATION: MEDI4166 was associated with an acceptable tolerability profile and significantly decreased LDL-cholesterol levels in a dose-dependent manner in overweight or obese patients with type 2 diabetes. However, there were no significant reductions in postprandial glucose levels at any dose of MEDI4166. TRIAL REGISTRATION: ClinicalTrials.gov NCT02524782 FUNDING: This study was funded by MedImmune LLC, Gaithersburg, MD, USA.


Assuntos
Anticorpos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Pró-Proteína Convertase 9/imunologia , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Resultado do Tratamento
5.
Lancet ; 391(10140): 2607-2618, 2018 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-29945727

RESUMO

BACKGROUND: Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes. METHODS: This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A1c [HbA1c] levels of 6·5-8·5% at screening) and a body-mass index between 27 kg/m2 and 40 kg/m2. An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A-C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 µg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 µg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC0-4 h) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585. FINDINGS: Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0-4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32·78% [90% CI -36·98 to -28·57] vs -10·16% [-14·10 to -6·21], and the mean difference was -22·62% [-28·40 to -16·85]; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3·84 kg [90% CI -4·55 to -3·12] vs -1·70 kg [-2·40 to -1·01] and mean difference of 2·14 kg [-3·13 to -1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group). INTERPRETATION: MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes. FUNDING: MedImmune.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Peptídeos/administração & dosagem , Perda de Peso/efeitos dos fármacos , Adulto , Idoso , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Hipoglicemiantes/efeitos adversos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Peptídeos/efeitos adversos
6.
Br J Clin Pharmacol ; 84(10): 2325-2335, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29926478

RESUMO

AIMS: MEDI0382 is a balanced glucagon-like peptide-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus and non-alcoholic steatohepatitis. The primary objective was to assess the safety of MEDI0382 in healthy subjects. METHODS: In this placebo-controlled, double-blind, Phase 1 study, healthy subjects (aged 18-45 years) were randomized (3:1) to receive a single subcutaneous dose of MEDI0382 or placebo after ≥8 h of fasting. The study consisted of six cohorts that received study drug at 5 µg, 10 µg, 30 µg, 100 µg, 150 µg or 300 µg. The primary objective was safety and tolerability. Secondary endpoints included assessments of pharmacokinetics and immunogenicity. All subjects were followed for up to 28 days. RESULTS: A total of 36 subjects received MEDI0382 (n = 6 per cohort) and 12 subjects received placebo (n = 2 per cohort). Treatment-emergent adverse events (TEAEs) occurred more frequently with MEDI0382 vs. placebo, which was mostly due to an increased occurrence at MEDI0382 doses ≥150 µg. All TEAEs were mild or moderate in severity. The most common TEAEs were vomiting, nausea and dizziness. There appeared to be a dose-dependent increase in heart rate with MEDI0382 treatment. MEDI0382 showed linear pharmacokinetic profile (time to maximum plasma concentration: 4.50-9.00 h; elimination half-life: 9.54-12.07 h). No immunogenicity was observed in the study. CONCLUSIONS: In this single-dose, Phase 1 study in healthy subjects, the safety and pharmacokinetic profiles of MEDI0382 support once-daily dosing and further clinical development of MEDI0382.


Assuntos
Hipoglicemiantes/efeitos adversos , Peptídeos/efeitos adversos , Adulto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Peptídeo 1 Semelhante ao Glucagon/agonistas , Meia-Vida , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Injeções Subcutâneas , Masculino , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Receptores de Glucagon/agonistas , Adulto Jovem
7.
Cardiovasc Diabetol ; 16(1): 113, 2017 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-28903775

RESUMO

BACKGROUND: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury. METHODS: In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). RESULTS: Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. CONCLUSIONS: The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Animais , Cardiotoxinas/efeitos adversos , Cardiotoxinas/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Dipeptídeos/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
8.
Diabetes Res Clin Pract ; 130: 24-33, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28554140

RESUMO

BACKGROUND: The impact of cardiovascular complications on health-related quality-of-life (HRQoL) in type 2 diabetes mellitus has not been clearly established. Using EQ5D utility data from SAVOR-TIMI 53, a large phase IV trial of saxagliptin versus placebo, we quantified the impact of cardiovascular and other major events on HRQoL. METHODS: EQ5D utilities were recorded annually and following myocardial infarction (MI) or stroke. Utilities among patients experiencing major cardiovascular events were analyzed using linear mixed-effects regression, adjusting for baseline characteristics (including EQ5D utility), and compared to those not experiencing major cardiovascular events. Mean utility decrements with standard errors (SE) were estimated as the difference in utility before and after the event. FINDINGS: The mean EQ5D utility of the sample was 0.776 at all time points, and did not differ by treatment. However, mean baseline and month 12 utilities among those with a major cardiovascular event were 0.751 and 0.714. Mean utilities were 0.691 within 3months of, 0.691 3-6months after, and 0.714 6-12months after, a major cardiovascular event. Cardiovascular event-specific utility decrements were 0.05 (0.007) for major cardiovascular events over the same time periods. Decrements of 0.051 (0.012; myocardial infarction), 0.111 (0.022; stroke), 0.065 (0.014; hospitalization for heart failure) 0.019 (0.024; hospitalization for hypoglycemia) were estimated; all coefficients were statistically significant. INTERPRETATION: Consistent with clinical outcomes reported elsewhere, saxagliptin did not improve HRQoL. Cardiovascular complications were associated with significantly decreased HRQoL, most substantial earlier after the event. FUNDING: BMS/AZ.


Assuntos
Adamantano/análogos & derivados , Doenças Cardiovasculares/terapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Adolescente , Adulto , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Hospitalização , Humanos , Hipoglicemia/complicações , Hipoglicemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
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 Obes Metab ; 19(7): 1045-1050, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28181728

RESUMO

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose <3.0 mmol/l (<54 mg/dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in >60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemia/etiologia , Medicina de Precisão , Atividades Cotidianas , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Idoso , Terapia Combinada/efeitos adversos , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Humanos , Hipoglicemia/fisiopatologia , Hipoglicemia/prevenção & controle , Hipoglicemia/terapia , Masculino , Refeições , Pessoa de Meia-Idade , Cooperação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Autorrelato , Índice de Gravidade de Doença
11.
Endocr Pract ; 23(3): 258-265, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27849380

RESUMO

OBJECTIVE: To determine if reduction in serum insulin with dapagliflozin plus saxagliptin or dapagliflozin add-on to metformin contributed to increased insulin clearance and to assess the effects of these treatments on ß-cell function. METHODS: Patients (glycated hemoglobin, 8 to 12%; 64 to 108 mmol/mol) were randomized to 24-week, double-blind treatment with saxagliptin 5 mg/day plus dapagliflozin 10 mg/day (n = 179), saxagliptin 5 mg/day plus placebo (n = 176), or dapagliflozin 10 mg/day plus placebo (n = 179) added to metformin. C-peptide to insulin ratio was used as an index of insulin clearance during a meal tolerance test, and ß-cell function was evaluated by Homeostasis Model Assessment 2. RESULTS: At 24 weeks, compared with baseline, saxagliptin + dapagliflozin and saxagliptin + placebo increased mean (95% confidence interval [CI]) C-peptide area under the curve (AUC0-180 min) (40.2 [9.2 to 71.3] ng/mL and 95.4 [63.4 to 127.4] ng/mL, respectively); no change was noted with dapagliflozin + placebo (14.5 [-17.6 to 46.8] ng/mL). Insulin AUC was reduced from baseline with saxagliptin + dapagliflozin (-1,120.4 [-1,633.9 to -606.9] µU/mL) and dapagliflozin + placebo (-1,018.6 [-1550.5 to -486.8] µU/mL) but increased with saxagliptin + placebo (661.2 [131.1 to 1,191.3] µU/mL). C-peptide to insulin ratio did not change versus baseline with saxagliptin + placebo but increased after saxagliptin + dapagliflozin and dapagliflozin + placebo, largely due to decreased insulin AUC with dapagliflozin. All treatments improved ß-cell function (mean change [95% CI] from baseline, saxagliptin+dapagliflozin: 20.6% [16.5% to 24.8%]; dapagliflozin + placebo: 17.0% [12.7% to 21.4%]; saxagliptin + placebo: 11.0% [6.6% to 15.5%]). CONCLUSION: Increased C-peptide to insulin ratio with saxagliptin + dapagliflozin and dapagliflozin + placebo add-on to metformin compared with saxagliptin + placebo add-on to metformin suggests that dapagliflozin increases insulin clearance and may contribute to lower circulating insulin. All treatments improved ß-cell function, with the greatest improvements with saxagliptin + dapagliflozin and dapagliflozin + placebo. ABBREVIATIONS: A1c = glycated hemoglobin AUC0-180 min = area under the curve from 0 to 180 minutes HOMA-2ß = homeostasis model assessment-2 ß-cell function SGLT-2 = sodium-glucose cotransporter-2 T2D = type 2 diabetes.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/uso terapêutico , Dipeptídeos/uso terapêutico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/sangue , Insulina/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Adamantano/uso terapêutico , Idoso , Área Sob a Curva , Glicemia/análise , Peptídeo C/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Transportador 2 de Glucose-Sódio
12.
Diabetes Care ; 40(1): 69-76, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27797925

RESUMO

OBJECTIVE: Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy. RESEARCH DESIGN AND METHODS: We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESULTS: At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA1c (r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well. CONCLUSIONS: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.


Assuntos
Adamantano/análogos & derivados , Albuminúria/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Dipeptídeos/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Adamantano/administração & dosagem , Idoso , Albuminúria/etiologia , Glicemia/efeitos dos fármacos , Creatinina/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Albumina Sérica/análise
13.
Clin Ther ; 38(12): 2578-2588, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27823868

RESUMO

PURPOSE: The management of hyperglycemia is challenging in older patients with type 2 diabetes owing to excess fragility and risk for adverse outcomes should hypoglycemia episodes occur. We evaluated baseline ß-cell function as a potential risk factor for the development of hypoglycemia when saxagliptin or glimepiride was added in patients aged ≥65 years whose type 2 diabetes was poorly controlled on stable metformin monotherapy. METHODS: A post hoc analysis of data from the GENERATION (Efficacy and Tolerability of Saxagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes: A Randomized, Controlled Study) trial, which enrolled 720 patients aged ≥65 years, was conducted. ß-Cell function was assessed using homeostasis model assessment-2%ß (HOMA-2%ß). FINDINGS: The percentage of patients experiencing any hypoglycemia event (ie, symptomatic event or event of plasma glucose concentration <54 mg/dL regardless of symptoms) was lower with saxagliptin compared with glimepiride (5.8% vs 34.8%). Regardless of treatment, patients with lower (median HOMA-2%ß ≤39.1% [≤median]) versus higher (HOMA-2%ß above median value [>median]) baseline ß-cell function had a higher hypoglycemia event rate (1.27 vs 0.82 events/patient-year; adjusted incidence rate ratio [IRR] = 1.800; 95% CI, 1.501-2.159). In patients receiving glimepiride, the hypoglycemia event rate was higher in patients with baseline HOMA-2%ß ≤median versus >median (2.29 vs 1.60 events/patient-year; adjusted IRR = 1.737; 95% CI, 1.439-2.097); corresponding saxagliptin hypoglycemia event rates were too low to draw meaningful conclusions (0.16 vs 0.09 events/patient-year; adjusted IRR = 2.457; 95% CI, 1.148-5.256). The association between lower ß-cell function at baseline and increased prevalence of hypoglycemia was particularly strong in patients aged ≥75 years (adjusted IRR = 2.409; 95% CI, 1.686-3.442; P < 0.001), although it was also significant in patients aged 65 to <75 years old (adjusted IRR, 1.654; 95% CI, 1.339-2.043; P < 0.001). IMPLICATIONS: In patients with lower ß-cell function, the addition of a sulfonylurea to a metformin regimen was associated with an increased risk for hypoglycemia compared with that in patients with higher ß-cell function; low hypoglycemia event rates with the addition of saxagliptin limited equivalent assessments. These findings in older patients are especially relevant because morbidity associated with hypoglycemia is higher in this age group. ClinicalTrials.gov identifier: NCT01006603 (ClinicalTrials.gov).


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Adamantano/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hiperglicemia/fisiopatologia , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
14.
JAMA Cardiol ; 1(9): 989-998, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27681000

RESUMO

Importance: Cardiac biomarkers provide insights into pathophysiologic processes and offer an attractive strategy for the assessment of cardiovascular risk. Objective: To assess the incremental prognostic value of biomarkers that reflect different pathophysiologic processes in patients with type 2 diabetes. Design, Setting, and Participants: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 is a randomized, double-blind, placebo-controlled clinical trial that evaluated the safety of saxagliptin vs placebo in 16 492 outpatients with type 2 diabetes with overt cardiovascular disease (CVD) or multiple risk factors. In this secondary analysis, widely used biomarkers were evaluated to ascertain whether they would provide incremental prognostic value in the risk stratification. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years). The study was performed from May 10, 2010, to June 15, 2013. Interventions: Randomization to saxagliptin vs placebo in addition to standard care. Main Outcomes and Measures: Concentrations of high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein were analyzed continuously and by established cut points. Cardiovascular death, myocardial infarction, ischemic stroke, and hospitalization for heart failure (HF) were adjudicated by a blinded events committee. Results: Of the 16 492 patients, 5455 (33.1%) were female and 11 037 (66.9%) were male. Mean (SD) age was 65.0 (8.5) years (range, 39-99 years). Baseline biomarkers were measured in 12 310 patients. Elevated levels of each biomarker were associated significantly with increased risk for all cardiovascular end points. When added to clinical variables, biomarkers significantly improved the discrimination and appropriate reclassification of risk. Elevated high-sensitivity troponin T was associated with an increased risk of cardiovascular death (adjusted hazard ratio [AHR], 3.07; 95% CI, 2.35-4.02; P < .001), myocardial infarction (AHR, 2.13; 95% CI, 1.69-2.67; P < .001), and hospitalization for HF (AHR, 3.85; 95% CI, 2.82-5.27; P < .001). Elevated N-terminal pro-B-type natriuretic peptide was also associated with an increased risk of cardiovascular death (AHR, 3.09; 95% CI, 2.46-3.89; P < .001), myocardial infarction (AHR, 1.95; 95% CI, 1.51-2.53; P < .001), and hospitalization for HF (AHR, 3.92; 95% CI, 3.11-4.92; P < .001). Elevated high-sensitivity C-reactive protein was more weakly associated with an increased risk of cardiovascular death (AHR, 1.49; 95% CI, 1.22-1.82; P < .001) and hospitalization for HF (AHR, 1.47; 95% CI, 1.20-1.81; P < .001). Consistent results were seen in patients with or without established CVD. Conclusions and Relevance: A substantial proportion of patients with stable type 2 diabetes with established CVD or multiple clinical risk factors have evidence of ongoing myocardial injury, hemodynamic stress, or systemic inflammation. Biomarker risk stratification thus challenges the traditional differentiation between primary and secondary prevention based simply on clinical history. Strategies to improve risk stratification in patients with type 2 diabetes, with or without CVD, should consider incorporation of biomarker data into standard risk algorithms. Trial Registration: clinicaltrials.gov Identifier: NCT01107886.

15.
Diabetes Ther ; 7(3): 527-35, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27402391

RESUMO

INTRODUCTION: Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). The recommended dose of the dipeptidyl peptidase-4 inhibitor saxagliptin is 2.5 mg in patients with moderate or severe renal impairment (creatinine clearance ≤50 mL/min). In this post hoc analysis, we assessed the effect of saxagliptin 2.5 and 5 mg/day versus placebo on glycemic measures in patients with T2D and estimated glomerular filtration rate 45-60 mL/min/1.73 m(2). METHODS: Efficacy and safety data were pooled from nine 24-week, randomized, placebo-controlled clinical trials. RESULTS: The majority (56-61%) of patients were women aged <65 years with glycated hemoglobin (A1C) 8.1-8.2%; half of the patients had a T2D duration ≥5 years. Mean change from baseline in A1C was significantly greater with saxagliptin 2.5 (-0.6%, P = 0.036 vs placebo) and 5 mg/day (-0.9%, P < 0.001 vs placebo) compared with placebo (-0.2%). There were numerically greater reductions in fasting plasma glucose and 2-h postprandial glucose, and a significantly greater proportion of patients achieved A1C <7% with saxagliptin 5 mg/day (44.8%) compared with placebo (20.0%, P = 0.004 vs placebo). The incidence of hypoglycemia was not significantly different across groups (16.2% in the saxagliptin 5-mg/day, 12.2% in the saxagliptin 2.5-mg/day, and 11.3% in the placebo groups). CONCLUSION: These results suggest that saxagliptin 2.5 and 5 mg/day improve glycemic control and are generally well tolerated in patients with T2D and moderate CKD. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00121641, NCT00316082, NCT00698932, NCT00918879, NCT00121667, NCT00661362, NCT00313313, NCT00295633, NCT00757588. FUNDING: AstraZeneca, Gaithersburg, MD, USA.

16.
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
17.
Am J Med ; 129(3): 340.e1-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26524706

RESUMO

BACKGROUND: The effect of saxagliptin on cardiovascular outcomes according to different hemoglobin A1c (HbA1c) levels has not been described. Thus, we analyzed the SAVOR-TIMI 53 trial to compare the cardiovascular effects of saxagliptin vs placebo according to baseline HbA1c. METHODS: A total of 16,492 patients with type 2 diabetes (HbA1c 6.5%-12.0% in the 6 months before randomization) and either a history of established cardiovascular disease or multiple risk factors for atherosclerosis were randomized to saxagliptin or placebo in addition to usual care. Patients were followed for a median of 2.1 years. The primary endpoint was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS: Patients were stratified by HbA1c at randomization into the following prespecified groups: <7%, 7%-<8%, 8%-<9%, and ≥9%. Baseline HbA1c ≥7% was associated with increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (adjusted hazard ratio [HR(adj)] 1.35; 95% confidence interval [CI], 1.17-1.58) but not hospitalization for heart failure (HR(adj) 1.09; 95% CI, 0.88-1.36). Saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke in patients with HbA1c <7% (HR 1.01; 95% CI, 0.78-1.31), 7%-<8% (HR 0.98; 95% CI, 0.80-1.20), 8%-<9% (HR 1.09; 95% CI, 0.85-1.39), ≥9% (HR 0.95; 95% CI, 0.77-1.18) (P-interaction = .89). CONCLUSIONS: Baseline HbA1c is associated with increased risk of macrovascular events but not hospitalization for heart failure. There was no heterogeneity in the effect of saxagliptin on cardiovascular events by baseline HbA1c, with cardiovascular death, myocardial infarction, or ischemic stroke neither increased nor decreased across the spectrum of baseline HbA1c values.


Assuntos
Adamantano/análogos & derivados , Doenças Cardiovasculares/mortalidade , Dipeptídeos/uso terapêutico , Hemoglobina A Glicada/análise , Incretinas/uso terapêutico , Infarto do Miocárdio/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Adamantano/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Risco
18.
Diabetes Care ; 38(11): 2142-50, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26358285

RESUMO

OBJECTIVE: Patients with type 2 diabetes have an increased risk of bone fractures, the predisposing factors for which are unknown. Treatment with thiazolidinediones (TZDs) further increases the incidence of osteoporotic fractures. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, fractures were considered an adverse event of special interest, and information regarding fractures was collected. RESEARCH DESIGN AND METHODS: We compared the incidence of fractures among the 8,280 patients who were assigned to treatment with saxagliptin with that in the 8,212 patients who were assigned to placebo. We further analyzed the participants' baseline characteristics and fracture risk. RESULTS: During a median follow-up of 2.1 years, 241 patients (2.9%) in the saxagliptin group and 240 (2.9%) in the placebo group experienced a fracture (hazard ratio [HR] 1.00 [95% CI 0.83-1.19]). Event rates for fractures were the same in both treatment arms: 14.7 per 1,000 patient-years in the entire population and 14.0 in the on-treatment population (first event only). Fracture risk was similar in patients treated with saxagliptin or placebo across different subgroups defined by race, cardiovascular risk, and renal function. A multivariable Cox regression analysis showed that risk of fracture was associated with female sex (P < 0.0001), longer diabetes duration (P < 0.0001), older age (P = 0.002), major hypoglycemic events (P = 0.01), noncompliance with study drug (P = 0.01), and treatment with TZDs (P = 0.03). CONCLUSIONS: In a large population of older patients with type 2 diabetes, treatment with saxagliptin was not associated with an increased risk of fractures. The association between longer diabetes duration and increased risk of bone fracture is an intriguing finding.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/complicações , Dipeptídeos/efeitos adversos , Hipoglicemiantes/efeitos adversos , Infarto do Miocárdio/complicações , Fraturas por Osteoporose/epidemiologia , Tiazolidinedionas/efeitos adversos , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Dipeptídeos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/etiologia , Fatores de Risco , Tiazolidinedionas/uso terapêutico
19.
Diabetes Care ; 38(11): 2018-24, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26324329

RESUMO

OBJECTIVE: The objective of this study was to assess the efficacy and safety of triple therapy with saxagliptin add-on versus placebo add-on to dapagliflozin plus metformin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients on stable metformin (≥1,500 mg/day) for ≥8 weeks with glycated hemoglobin (HbA1c) 8.0-11.5% (64-102 mmol/mol) at screening received open-label dapagliflozin (10 mg/day) plus metformin immediate release (IR) for 16 weeks. Patients with inadequate glycemic control (HbA1c 7-10.5% [53-91 mmol/mol]) were then randomized to receive placebo (n = 153) or saxagliptin 5 mg/day (n = 162) in addition to background dapagliflozin plus metformin IR. The primary efficacy end point was change in HbA1c from baseline to week 24. RESULTS: There was a significantly greater reduction in HbA1c at 24 weeks with saxagliptin add-on (-0.51% [-5.6 mmol/mol]) versus placebo (-0.16% [-1.7 mmol/mol]) add-on to dapagliflozin plus metformin (difference, -0.35% [95% CI -0.52% to -0.18%] and -3.8 [-5.7 to -2.0 mmol/mol], respectively; P < 0.0001). Reductions in fasting plasma glucose and 2-h postprandial glucose were similar between treatment arms. A larger proportion of patients achieved HbA1c <7% (53 mmol/mol) with saxagliptin add-on (35.3%) versus placebo add-on (23.1%) to dapagliflozin plus metformin. Adverse events were similar between treatment groups. Episodes of hypoglycemia were infrequent in both treatment arms, and there were no episodes of major hypoglycemia. CONCLUSIONS: Triple therapy with the addition of saxagliptin to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with type 2 diabetes inadequately controlled with dapagliflozin plus metformin.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/administração & dosagem , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adulto , Idoso , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Dipeptídeos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento
20.
Curr Diab Rep ; 15(11): 87, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26370698

RESUMO

Owing to the close association of cardiovascular (CV) disease with type 2 diabetes and the uncertainty surrounding the CV safety of antidiabetes agents, in 2008 the Food and Drug Administration issued guidance for the demonstration of CV safety for new antidiabetes drugs. Recently the results from CV outcomes trials of three dipeptidyl peptidase-4 (DPP-4) inhibitors and a glucagon-like peptide-1 receptor agonist have been reported. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial, and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the safety of saxagliptin, alogliptin, and sitagliptin, respectively, in patients with type 2 diabetes with CV disease or at high risk for CV disease. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) assessed the safety of lixisenatide in patients with type 2 diabetes and a recent acute coronary syndrome event. The results show that these agents neither increased nor deceased major adverse CV events (CV death, nonfatal myocardial infarction, and nonfatal stroke) compared with placebo. However, the resources needed to conduct these studies may detract from the ability to understand the potential long-term benefit and risk in the majority of patients that are candidates for use of these medications.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Piperidinas/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Resultado do Tratamento , Uracila/análogos & derivados , Uracila/uso terapêutico
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