RESUMO
BACKGROUND: The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk. METHODS: 9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed. RESULTS: A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria. CONCLUSIONS: The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors. Trial Registration clinicaltrials.gov NCT01394952.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias , Albuminas , Albuminúria/complicações , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Creatinina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Taxa de Filtração Glomerular , Humanos , Rim , Fatores de RiscoRESUMO
OBJECTIVE: Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. RESEARCH DESIGN AND METHODS: Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. RESULTS: Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81-1.05) vs. 0.78 (CI 0.61-0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. CONCLUSION: This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Metformina , Doenças Vasculares , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1 , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Humanos , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão , Resultado do TratamentoRESUMO
BACKGROUND: The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial. METHODS: Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model. RESULTS: Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively). CONCLUSIONS: Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952.
Assuntos
Albuminúria/prevenção & controle , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Albuminúria/diagnóstico , Albuminúria/urina , Biomarcadores/sangue , Biomarcadores/urina , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Creatinina/urina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/metabolismo , Fatores de Risco de Doenças Cardíacas , Humanos , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Medição de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/prevenção & controleRESUMO
BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51â820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Albuminúria/prevenção & controle , Creatinina/urina , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants METHODS: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models. RESULTS: Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028]. CONCLUSIONS: These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gouv . Unique Identifier NCT01394952).
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Incretinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Método Duplo-Cego , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Fatores de Risco de Doenças Cardíacas , Humanos , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Incretinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Medição de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
In patients with type 2 dibetes and moderate-to-severe chronic kidney disease, dulaglutide treatment led to body weight (BW) loss and lesser eGFR decline compared to insulin glargine. As BW may affect muscle mass, creatinine-based eGFR can be altered independently of kidney function. Cystatin C-based eGFR is not affected by muscle mass. The objective of this post-hoc analysis was to determine whether the lesser eGFR decline with dulaglutide was related to BW loss. Baseline characteristics were similar between treatments ([mean ± SD] age, 64.6 ± 8.6 years; women, 48%; BW, 89.1 ± 17.7 kg; eGFR [CKD-EPI-cystatin C] 38 ± 14 mL/min/1.73m2 ). BW decreased with dulaglutide 1.5 and 0.75 mg and increased with insulin glargine ([LSM change (SE)], -2.66 [0.47] kg and -1.71 [0.45] vs 1.57 [0.43] kg; P < 0.001). Changes in eGFR were not significant with dulaglutide 1.5 and 0.75 mg, but eGFR significantly decreased with insulin glargine (eGFR-CKD-EPI-cystatin C [LSM change (95%CI)], -0.7 [-2.5, 1.0] and -0.7 [-2.4, 1.1] vs -3.3 [-5.1, -1.6] mL/min/1.73 m2 ; P ≤ 0.037 vs glargine). Changes in BW did not correlate with changes in eGFR-CKD-EPI-cystatin C (r = -0.041; n = 471; P = 0.379) or eGFR-CKD-EPI-creatinine (r = -0.074; n = 473; P = 0.106). In conclusion, the lesser decline in eGFR observed with dulaglutide was not influenced by BW loss.
Assuntos
Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2 , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes , Fragmentos Fc das Imunoglobulinas , Proteínas Recombinantes de Fusão , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/farmacologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Insuficiência Renal Crônica/complicaçõesRESUMO
AIM: To examine the generalizability of results from glucagon-like peptide-1 receptor agonist (GLP-1 RA) cardiovascular outcome trials (CVOTs) in the US type 2 diabetes (T2D) population. MATERIALS AND METHODS: Patients enrolled or eligible for inclusion in four CVOTs (EXSCEL, LEADER, REWIND, and SUSTAIN-6) were examined in reference to a retrospective clinical database weighted to match the age and sex distribution of the US adult T2D population. We descriptively compared key baseline characteristics of the populations enrolled in each trial to those of the reference population and estimated the proportions of individuals in the reference population represented by those in the trials for each characteristic. We also estimated the proportions of individuals in the reference population that might have been enrolled in each trial based upon meeting the trial inclusion and exclusion (I/E) criteria. RESULTS: No trial's enrolled population perfectly matched the reference population in key characteristics. The EXSCEL population most closely matched in mean age (62.7 vs. 60.5 years) and percentage with estimated glomerular filtration rate <60 (18.6 vs. 17.3%), while REWIND most closely matched in HbA1c, sex distribution, and proportion with a prior myocardial infarction. Based on I/E criteria, 42.6% of the reference population were eligible for enrolment in REWIND, versus 15.9% in EXSCEL, 13.0% in SUSTAIN-6, and 12.9% in LEADER. CONCLUSIONS: Although none of the trials are fully representative of the general population, among the four trials examined, results from baseline REWIND were found to be more generalizable to the US adult T2D population than those of other GLP-1 RA CVOTs.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Estudos Retrospectivos , Estados UnidosRESUMO
The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Incretinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/mortalidade , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/mortalidade , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Incretinas/administração & dosagem , Incretinas/efeitos adversos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Mortalidade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Projetos de Pesquisa , Fatores de RiscoRESUMO
OBJECTIVE: The glucagon-like peptide-1 receptor agonist dulaglutide reduced MACE in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. This article expores the relationship of selected biomarkers to both dulaglutide and major adverse cardiovascular events (MACE). RESEARCH DESIGN AND METHODS: In this post hoc analysis, stored fasting baseline and 2-year plasma samples from 824 REWIND participants with MACE during follow-up and 845 matched non-MACE participants were analyzed for 2-year changes in 19 protein biomarkers. Two-year changes in 135 metabolites were also analyzed in 600 participants with MACE during follow-up and in 601 matched non-MACE participants. Linear and logistic regression models were used to identify proteins that were associated with both dulaglutide treatment and MACE. Similar models were used to identify metabolites that were associated with both dulaglutide treatment and MACE. RESULTS: Compared with placebo, dulaglutide was associated with a greater reduction or lesser 2-year rise from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein, and a greater 2-year rise in C-peptide. Compared with placebo, dulaglutide was also associated with a greater fall from baseline in 2-hydroxybutyric acid and a greater rise in threonine (P < 0.001). Increases from baseline in two of the proteins (but neither metabolite) were associated with MACE, including NT-proBNP (OR 1.267; 95% CI 1.119, 1.435; P < 0.001) and GDF-15 (OR 1.937; 95% CI 1.424, 2.634; P < 0.001). CONCLUSIONS: Dulaglutide was associated with a reduced 2-year rise from baseline of NT-proBNP and GDF-15. Higher rises of these biomarkers were also associated with MACE.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Fator 15 de Diferenciação de Crescimento/uso terapêutico , Método Duplo-Cego , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Doenças Cardiovasculares/complicações , Biomarcadores , Estudos de Casos e ControlesRESUMO
AIMS: People with diabetes are at high risk for cardiovascular events including heart failure (HF). We examined the effect of the glucagon-like peptide 1 agonist dulaglutide on incident HF events and other cardiovascular outcomes in those with or without prior HF in the randomized placebo-controlled Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. METHODS AND RESULTS: The REWIND major adverse cardiovascular event (MACE) outcome was the first occurrence of a composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes). In this post-hoc analysis, a HF event was defined as an adjudication-confirmed hospitalization or urgent evaluation for HF. Of the 9901 participants studied over a median follow-up of 5.4 years, 213/4949 (4.3%) randomly assigned to dulaglutide and 226/4952 (4.6%) participants assigned to placebo experienced a HF event (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.77-1.12; p = 0.456). In the 853 (8.6%) participants with HF at baseline, there was no change in either MACE or HF events with dulaglutide as compared to participants without HF (p = 0.44 and 0.19 for interaction, respectively). Combined cardiovascular death and HF events were marginally reduced with dulaglutide compared to placebo (HR 0.88, 95% CI 0.78-1.00; p = 0.050) but unchanged in patients with and without HF at baseline (p = 0.31). CONCLUSIONS: Dulaglutide was not associated with a reduction in HF events in patients with type 2 diabetes regardless of baseline HF status over 5.4 years of follow-up.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/induzido quimicamente , Resultado do Tratamento , Incretinas/uso terapêutico , Doenças Cardiovasculares/epidemiologiaRESUMO
CONTEXT: Low cognitive scores are risk factors for cardiovascular outcomes. Whether this relationship is stronger using novel cognitive indices is unknown. METHODS: Participants in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial who completed both the Montreal Cognitive Assessment (MoCA) score and Digit Substitution Test (DSST) at baseline (Nâ =â 8772) were included. These scores were used to identify participants with baseline substantive cognitive impairment (SCI), defined as a baseline score on either the MoCA or DSSTâ ≥â 1.5 SD below either score's country-specific mean, or SCI-GM, which was based on a composite index of both scores calculated as their geometric mean (GM), and defined as a score that wasâ ≥â 1.5 SD below their country's average GM. Relationships between these measures and incident major adverse cardiovascular events (MACE), and either stroke or death were analyzed. RESULTS: Compared with 7867 (89.7%) unaffected participants, the 905 (10.3%) participants with baseline SCI had a higher incidence of MACE (unadjusted hazard ratio [HR] 1.34; 95% CI 1.11, 1.62; Pâ =â 0.003), and stroke or death (unadjusted HR 1.60; 95% CI 1.33, 1.91; Pâ <â 0.001). Stronger relationships were noted for SCI-GM and MACE (unadjusted HR 1.61; 95% CI 1.28, 2.01; Pâ <â 0.001), and stroke or death (unadjusted HR 1.85; 95% CI 1.50, 2.30; Pâ <â 0.001). For SCI-GM but not SCI, all these relationships remained significant in models that adjusted for up to 10 SCI risk factors. CONCLUSION: Country-standardized SCI-GM was a strong independent predictor of cardiovascular events in people with type 2 diabetes in the REWIND trial.
Assuntos
Doenças Cardiovasculares , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Acidente Vascular Cerebral , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/etiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/etiologiaRESUMO
BACKGROUND: Long-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. Glucagon-like peptide 1 receptor agonists (GLP-1RA) lower glucose, but the long-term impact on retinopathy is unknown. GLP-1RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes. PURPOSE: To examine the associations between retinopathy, HbA1c, systolic blood pressure (SBP), and weight in GLP-1RA CVOTs. DATA SOURCES: Systematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes. STUDY SELECTION: Published trial reports were used as the primary data sources. DATA EXTRACTION: HbA1c, SBP, and weight data throughout follow-up by treatment group were extracted. DATA SYNTHESIS: Random-effects model meta-analysis showed no association between GLP-1RA treatment and retinopathy (odds ratio [OR] 1.10; 95% CI 0.93, 1.30), with high heterogeneity between studies (I 2 = 52.2%; Q statistic P = 0.063). Univariate meta-regression showed an association between retinopathy and average HbA1c reduction during the overall follow-up (slope = 0.77, P = 0.007), but no relationship for SBP or weight. Sensitivity analyses for HbA1c showed a relationship at 3 months (P = 0.006) and 1 year (P = 0.002). A 0.1% (1.09 mmol/mol) increase in HbA1c reduction was associated with 6%, 14%, or 8% increased Ln(OR) for retinopathy at the 3-month, 1-year, and overall follow-up, respectively. LIMITATIONS: CVOTs were not powered to assess retinopathy outcomes and differed in retinopathy-related criteria and methodology. The median follow-up of 3.4 years is short compared with the onset of retinopathy. CONCLUSIONS: HbA1c reduction was significantly associated with increased retinopathy risk in meta-regression for GLP-1RA CVOTs. The magnitude of HbA1c reduction was correlated with retinopathy risk in people with diabetes and additional cardiovascular risk factors, but the long-term impact of improved glycemic control on retinopathy was unmeasured in these studies. Retinopathy status should be assessed when intensifying glucose-lowering therapy.
Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Retinopatia Diabética/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hemoglobinas Glicadas , Humanos , HipoglicemiantesRESUMO
Background: In the AWARD-7 trial of participants with type 2 diabetes (T2DM) and moderate-to-severe CKD, dulaglutide (DU) treatment slowed decline in eGFR compared with insulin glargine (IG). Treatment with doses of either DU or IG resulted in similar levels of glycemic control and BP. The aim of this analysis was to determine the risk of clinical event outcomes between treatment groups. Methods: Participants with T2DM and CKD categories 3-4 were randomized (1:1:1) to 0.75 or 1.5 mg DU weekly or IG daily as basal therapy, with titrated insulin lispro, for 1 year. The time to occurrence of the composite outcome of ≥40% eGFR decline, ESKD, or death due to kidney disease was compared using a Cox proportional-hazards model. Results: Patients treated with 1.5 mg DU weekly versus IG daily for 1 year had a lower risk of ≥40% eGFR decline or ESKD events in the overall study population (5% versus 11%; hazard ratio, 0.45; 95% CI, 0.20 to 0.97; P=0.04). Most events occurred in the subset of patients with macroalbuminuria, where risk of the composite outcome was substantially lower for 1.5 mg DU versus IG (7% versus 22%; hazard ratio, 0.25; 95% CI, 0.10 to 0.68; P=0.006). No deaths due to kidney disease occurred. Conclusions: Treatment with 1.5 mg DU weekly was associated with a clinically relevant risk reduction of ≥40% eGFR decline or ESKD compared with IG daily, particularly in the macroalbuminuria subgroup of participants with T2DM and moderate-to-severe CKD.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Humanos , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas , Insulina Glargina/efeitos adversos , Proteínas Recombinantes de Fusão , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
CONTEXT: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed. OBJECTIVE: This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥â 65 and <â 65 years). METHODS: A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes). RESULTS: There were 5256 randomly assigned patients who were 65 years or older (meanâ =â 71.0), and 4645 were younger than 65 years (meanâ =â 60.7). Baseline characteristics were similar in randomized treatment groups. Dulaglutide treatment showed a similar reduction in the incidence (11% vs 13%) of MACE in older vs younger patients. The rate of permanent study drug discontinuation, incidence of all-cause mortality, hospitalizations for heart failure, severe hypoglycemia, severe renal or urinary events, and serious gastrointestinal events were similar between randomized treatment groups within each age subgroup. The incidence rate of serious cardiac conduction disorders was numerically higher in the dulaglutide group compared to placebo within each age subgroup but the difference was not statistically significant. CONCLUSION: Dulaglutide had similar efficacy and safety in REWIND in patients65 years and older and those younger than 65 years.
Assuntos
Envelhecimento/fisiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/patologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes. METHODS: The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85-0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18-1·05, p=0·006). INTERPRETATION: Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes. FUNDING: Eli Lilly and Company.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Disfunção Erétil/epidemiologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Idoso , Biomarcadores/análise , Glicemia/análise , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/patologia , Método Duplo-Cego , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/patologia , Feminino , Seguimentos , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA1c was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m2. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, we screened 12â133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62-0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59-0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55-1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79-0·98; p=0·017) and disabling stroke (0·74, 0·56-0·99; p=0·042). The degree of disability after stroke did not differ by treatment group. INTERPRETATION: Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity. FUNDING: Eli Lilly and Company.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hemoglobinas Glicadas/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Método Duplo-Cego , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Incretinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. METHODS: REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85-1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018). INTERPRETATION: Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. FUNDING: Eli Lilly and Company.
Assuntos
Disfunção Cognitiva/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Disfunção Cognitiva/etiologia , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, restricting treatment options for patients with kidney disease. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys, and confers a lower risk of hypoglycaemia than does insulin. We assessed the efficacy and safety of dulaglutide in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. METHODS: AWARD-7 was a multicentre, open-label trial done at 99 sites in nine countries. Eligible patients were adults with type 2 diabetes and moderate-to-severe chronic kidney disease (stages 3-4), with an HbA1c of 7·5-10·5%, and who were being treated with insulin or insulin plus an oral antihyperglycaemic drug and were taking a maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Participants were randomly assigned (1:1:1) by use of a computer-generated random sequence with an interactive response system to once-weekly injectable dulaglutide 1·5 mg, once-weekly dulaglutide 0·75 mg, or daily insulin glargine as basal therapy, all in combination with insulin lispro, for 52 weeks. Insulin glargine and lispro doses were titrated as per an adjustment algorithm; dulaglutide doses were masked to participants and investigators. The primary outcome was HbA1c at 26 weeks, with a 0·4% non-inferiority margin. Secondary outcomes included estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). The primary analysis population was all randomly assigned patients who received at least one dose of study treatment and had at least one post-randomisation HbA1c measurement. The safety population was all patients who received at least one dose of study treatment and had any post-dose data. This study is registered with ClinicalTrials.gov, number NCT01621178. FINDINGS: Between Aug 15, 2012, and Nov 30, 2015, 577 patients were randomly assigned, 193 to dulaglutide 1·5 mg, 190 to dulaglutide 0·75 mg, and 194 to insulin glargine. The effects on HbA1c change at 26 weeks of dulaglutide 1·5 mg and 0·75 mg were non-inferior to those of insulin glargine (least squares mean [LSM] -1·2% [SE 0·1] with dulaglutide 1·5 mg [183 patients]; -1·1% [0·1] with dulaglutide 0·75 mg [180 patients]; -1·1% [0·1] with insulin glargine [186 patients]; one-sided p≤0·0001 for both dulaglutide doses vs insulin glargine). The differences in HbA1c concentration at 26 weeks between dulaglutide and insulin glargine treatments were LSM difference -0·05% (95% CI -0·26 to 0·15, p<0·0001) with dulaglutide 1·5 mg and 0·02% (-0·18 to -0·22, p=0·0001) with dulaglutide 0·75 mg. HbA1c-lowering effects persisted to 52 weeks (LSM -1·1% [SE 0·1] with dulaglutide 1·5 mg; -1·1% [0·1] with dulaglutide 0·75 mg; -1·0% [0·1] with insulin glargine). At 52 weeks, eGFR was higher with dulaglutide 1·5 mg (Chronic Kidney Disease Epidemiology Collaboration equation by cystatin C geometric LSM 34·0 mL/min per 1·73 m2 [SE 0·7]; p=0·005 vs insulin glargine) and dulaglutide 0·75 mg (33·8 mL/min per 1·73 m2 [0·7]; p=0·009 vs insulin glargine) than with insulin glargine (31·3 mL/min per 1·73 m2 [0·7]). At 52 weeks, the effects of dulaglutide 1·5 mg and 0·75 mg on UACR reduction were not significantly different from that of insulin glargine (LSM -22·5% [95% CI -35·1 to -7·5] with dulaglutide 1·5 mg; -20·1% [-33·1 to -4·6] with dulaglutide 0·75 mg; -13·0% [-27·1 to 3·9] with insulin glargine). Proportions of patients with any serious adverse events were similar across groups (20% [38 of 192] with dulaglutide 1·5 mg, 24% [45 of 190] with dulaglutide 0·75 mg, and 27% [52 of 194] with insulin glargine). Dulaglutide was associated with higher rates of nausea (20% [38 of 192] with dulaglutide 1·5 mg and 14% [27 of 190] with 0·75 mg, vs 5% [nine of 194] with insulin glargine) and diarrhoea (17% [33 of 192] with dulaglutide 1·5 mg and 16% [30 of 190] with 0·75 mg, vs 7% [14 of 194] with insulin glargine) and lower rates of symptomatic hypoglycaemia (4·4 events per patient per year with dulaglutide 1·5 mg and 4·3 with dulaglutide 0·75 mg, vs 9·6 with insulin glargine). End-stage renal disease occurred in 38 participants: eight (4%) of 192 with dulaglutide 1·5 mg, 14 (7%) of 190 with dulaglutide 0·75 mg, and 16 (8%) of 194 with insulin glargine. INTERPRETATION: In patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide produced glycaemic control similar to that achieved with insulin glargine, with reduced decline in eGFR. Dulaglutide seems to be safe to use to achieve glycaemic control in patients with moderate-to-severe chronic kidney disease. FUNDING: Eli Lilly and Company.
Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Insulina Glargina/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Glicemia/análise , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Seguimentos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Adulto JovemRESUMO
OBJECTIVE: Raloxifene hydrochloride is a selective estrogen receptor modulator that to date has not been shown to cause hypertriglyceridemia in normal, diabetic, or hypertriglyceridemic women. This study was designed to assess the effect of raloxifene on serum triglycerides in postmenopausal women who have a history of increased hypertriglyceridemia with oral estrogen therapy. RESEARCH DESIGN AND METHODS: This was a single-center, uncontrolled, open-label study investigating the effects of 8 weeks of raloxifene (60 mg/day) therapy on plasma lipids. The study subjects were 12 postmenopausal women, ages 49-73 years, with a documented history of oral estrogen-induced hypertriglyceridemia (serum triglycerides > or =3.39 mmol/l [> or =300 mg/dl]). RESULTS: At week 2 of the study, three (25%) of the subjects withdrew from the trial because they developed marked hypertriglyceridemia (>or =11.3 mmol/l [> or =1,000 mg/dl]) during raloxifene therapy. These three women had higher baseline triglyceride and glucose levels, were not being treated with lipid-lowering agents, and were more likely to have diabetes than the other study subjects. The remaining nine patients (75%) completed the 8-week trial and experienced a nonsignificant increase in mean triglyceride levels from baseline to end point. Raloxifene treatment also resulted in a significant 16% decrease in hepatic lipase activity and a 26% increase in HDL(2) levels (P = 0.013 and 0.03, respectively). CONCLUSIONS: Patients with a previous history of hypertriglyceridemia on oral estrogen therapy should have serum triglyceride levels monitored closely after beginning raloxifene therapy and may even require fibrate therapy before beginning raloxifene.