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BACKGROUND: As type 2 diabetes (T2D) progresses, intensification to combination therapies, such as iGlarLixi (a fixed-ratio GLP-1 RA and basal insulin combination), may be required. Here a simulation study was used to assess the effect of iGlarLixi administration timing (am vs pm) on blood sugar profiles. METHODS: Models of lixisenatide were built with a selection procedure, optimizing measurement fits and model complexity, and were included in a pre-existing T2D simulation platform containing glargine models. With the resulting tool, a simulated trial was conducted with 100 in-silico participants with T2D. Individuals were given iGLarLixi either before breakfast or before an evening meal for 2 weeks and daily glycemic profiles were analyzed. In the model, breakfast was considered the largest meal of the day. RESULTS: A similar percentage of time within 24 hours was spent with blood sugar levels between 70 to 180 mg/dL when iGlarLixi was administered pre-breakfast or pre-evening meal (73% vs 71%, respectively). Overall percent of time with blood glucose levels above 180 mg/dL within a 24-hour period was similar when iGlarLixi was administered pre-breakfast or pre-evening meal (26% vs 28%, respectively). Rates of hypoglycemia were low in both regimens, with a blood glucose concentration of below 70 mg/dL only observed for 1% of the 24-hour time period for either timing of administration. CONCLUSIONS: Good efficacy was observed when iGlarlixi was administered pre-breakfast; however, administration of iGlarlixi pre-evening meal was also deemed to be effective, even though in the model the size of the evening meal was smaller than that of the breakfast.
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Glicemia , Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Esvaziamento Gástrico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes , Insulina Glargina , PeptídeosRESUMO
Globally, nearly half of patients with type 2 diabetes (T2D) do not successfully achieve target HbA1c with basal insulin, despite meeting fasting plasma glucose (FPG) targets. In this post hoc analysis of the LixiLan-L study, we determined whether iGlarLixi, a fixed-ratio combination of insulin glargine Gla-100 (iGlar) and the glucagon-like peptide-1 receptor agonist lixisenatide (Lixi), addresses the challenge of reducing residual hyperglycaemia in patients with T2D. In LixiLan-L, a randomized, open-label study, 1018 patients with T2D on basal insulin for ≥6 months ± oral antidiabetes drugs entered a 6-week run-in period, during which they were switched to and/or optimized for a daily dose of iGlar while continuing only metformin. Following the run-in period, 736 patients were then randomized to receive iGlarLixi or were continued on iGlar for 30 weeks ± metformin. Residual hyperglycaemia was defined as HbA1c ≥ 7.0% despite FPG of <140 mg/dL. The proportion of patients with residual hyperglycaemia was similar in both treatment arms at screening (~~42%), and increased after the run-in period (~~62%). After 30 weeks, the proportion of patients with residual hyperglycaemia declined to 23.8% in the iGlarLixi versus 47.1% in the iGlar arm (P < .0001). The proportion of patients achieving both HbA1c (<7.0%) and FPG (<140 mg/dL) targets was higher in the iGlarLixi compared with the iGlar arm (50.3% vs. 27.4%, respectively; P < .0001). iGlarLixi effectively reduces residual hyperglycaemia in patients with T2D on basal insulin therapy.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Glicemia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêuticoRESUMO
AIM: To evaluate the efficacy of iGlarLixi by C-peptide levels and duration of diabetes in an exploratory analysis of the LixiLan-G study. METHODS: LixiLan-G was a 26-week, randomized, open-label study in adults with type diabetes (T2D) inadequately controlled while on a glucagon-like peptide-1 receptor agonist (GLP-1 RA), with metformin, with or without pioglitazone and/or a sodium-glucose co-transporter-2 inhibitor. This analysis investigated the efficacy of switching to iGlarLixi by fasting baseline quartile C-peptide levels and baseline quartile of duration of T2D compared with continued GLP-1 RA use. RESULTS: Change in glycated hemoglobin (HbA1c) from baseline to week 26 was significantly greater with iGlarLixi compared with continued GLP-1 RAs across all fasting C-peptide quartiles (-1.00% to -1.06% vs. -0.23% to -0.54% range, respectively) and irrespective of all T2D duration quartiles (-0.94% to -1.07% vs. -0.25% to -0.50% range). A significantly greater proportion of participants in the iGlarLixi arm achieved an HbA1c of <7% across all C-peptide quartiles (51%-73% range) than in the GLP-1 RA arm (19%-32% range). The greatest reductions in HbA1c in participants receiving iGlarLixi were observed in those with the shortest duration of disease, although consistently greater than reductions observed with continued GLP-1 RAs. Reductions in HbA1c were comparable across C-peptide quartiles within the iGlarLixi arm. CONCLUSIONS: The results of this study suggest that iGlarLixi is an effective treatment option, irrespective of C-peptide levels or duration of diabetes, in adults with insufficiently controlled T2D receiving GLP-1 RAs.
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Diabetes Mellitus Tipo 2 , Adulto , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina Glargina , PeptídeosRESUMO
INTRODUCTION: With longer duration and progression of type 2 diabetes (T2D), ß-cell function deteriorates and insulin therapy often becomes necessary. Glucagon-like peptide-1 receptor agonists such as lixisenatide that do not rely only on ß-cell function and glucagon suppression primarily, but also lower glucose by other (insulin-independent) mechanisms such as delayed gastric emptying, may be appropriate adjuvant therapy to basal insulin in patients with longstanding T2D. METHODS: We assessed the efficacy and safety of insulin glargine (iGlar) versus iGlarLixi, a fixed-ratio combination of iGlar and lixisenatide, stratified by quartiles (Q) of T2D duration (≤ 7.305 [Q1], > 7.305 to ≤ 10.75 [Q2], > 10.75 to ≤ 15.67 [Q3], and > 15.67 years [Q4]) in the LixiLan-L trial (N = 736). RESULTS: Across all quartiles, the reduction in glycated haemoglobin was greater with iGlarLixi versus iGlar, and the difference was most pronounced in patients with the longest duration (Q4; least squares mean difference [standard error] - 0.62 [0.13], P < 0.0001). Additionally, hypoglycaemia rates were significantly lower with iGlarLixi versus iGlar in patients in Q4 (3.3 vs. 6.9 events/patient-year, P < 0.0001). CONCLUSION: iGlarLixi lowered glycated haemoglobin more versus iGlar regardless of T2D duration, with benefit retained even among patients with the longest T2D duration.
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INTRODUCTION: Basal-bolus (BB) regimens are generally used to intensify basal insulin therapy in patients with type 2 diabetes (T2D) not meeting glycemic targets. However, drawbacks include multiple injection burden and risk of weight gain and hypoglycemia. A once-daily titratable fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi) may provide a simple, well-tolerated, and efficacious alternative. We compared these treatments in a post hoc propensity score matched analysis using randomized trial data. METHODS: From the LixiLan-L study, 195 patients who had been randomized to iGlarLixi were matched for age, sex, race, T2D duration, baseline body mass index, glycated hemoglobin (HbA1c), fasting plasma glucose, insulin dose, and metformin use to 195 patients who had been randomized to a BB regimen in the GetGoal Duo-2 trial. RESULTS: At study end, estimated treatment differences for reduction in HbA1c and weight change, and ratio of hypoglycemia events per patient-year (BB vs iGlarLixi) were - 0.28% (standard error 0.08, P = 0.0002), - 1.32 kg (standard error 0.30, P < 0.0001), and 2.85 (P < 0.0001), respectively, all favoring iGlarLixi over BB. Also, proportions of patients reaching individual and composite goals (HbA1c < 7% [< 53 mmol/mol], no weight gain, and no hypoglycemia) were higher in the iGlarLixi compared with the BB treatment group. Gastrointestinal side effects were more common with iGlarLixi. CONCLUSIONS: In patients with T2D inadequately controlled on basal insulin, iGlarLixi offers an effective alternative to BB regimen for reducing HbA1c, without increased risk of hypoglycemia and weight gain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02058160 (LixiLan-L trial); NCT01768559 (GetGoal Duo-2 trial). Plain language summary available for this article.
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Diabetic dyslipidaemia is a major risk factor for accelerated atherosclerosis. Glycaemic treatments that improve dyslipidaemia may help reduce the burden of atherosclerosis. This analysis investigated the effect of iGlarLixi [insulin glargine U100 (iGlar) and lixisenatide] versus iGlar on lipid profiles in patients with type 2 diabetes uncontrolled on basal insulin. Data from LixiLan-L were used to estimate changes in fasting lipid levels from baseline to week 30, overall and in patients stratified by achievement of glycaemic targets {2-hour postprandial glucose [≤10, >10 mmoL/L], fasting plasma glucose [≤6.1, >6.1 mmoL/L], HbA1c [≤7, >7% (≤53, >53 mmol/mol)]}. At week 30, median percentage change in triglycerides remained nearly unchanged (0.3% increase) with iGlarLixi versus a 6.5% increase with iGlar (P = 0.035; overall); similarly, trends towards better total and LDL cholesterol levels were observed with iGlarLixi versus iGlar. In patient subgroups achieving glycaemic targets, all lipid variables except for HDL cholesterol improved with iGlarLixi but not with iGlar. In summary, patients with type 2 diabetes uncontrolled on basal insulin showed improved fasting lipid profiles with iGlarLixi compared with iGlar, particularly when achieving glycaemic targets.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Peptídeos/uso terapêutico , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Insulina Glargina/administração & dosagem , Lipídeos/sangue , Peptídeos/administração & dosagemRESUMO
Objective: Type 2 diabetes (T2D) is more common in Hispanic than non-Hispanic white (NHW) populations worldwide, and ethnicity, among other factors, may affect response to therapy. The efficacy and safety of insulin glargine 100 units/mL (iGlar) and the fixed-ratio combination of iGlar and the glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi) was assessed in Hispanic and NHW patients with T2D from 25 countries. Methods: In this post hoc analysis, data from two 30-week randomized controlled trials comparing iGlar and iGlarLixi in patients with T2D uncontrolled on basal insulin ± oral antidiabetes drugs (OADs; LixiLan-L: NCT02058160) or uncontrolled on metformin ± OADs (LixiLan-O: NCT02058147) were evaluated. Results: Of the 1,512 patients included across trials, 301 were Hispanic and 1,211 NHW. Compared with iGlar, iGlarLixi resulted in greater reductions in glycated hemoglobin (A1C) and 2-hour postprandial glucose and a higher proportion of patients at target A1C <7.0% (<53 mmol/mol), regardless of ethnicity. Among NHWs from the LixiLan-L trial, documented symptomatic hypoglycemia (plasma glucose ≤70 mg/dL) rates were higher with iGlar compared with iGlarLixi (P = .06), whereas this trend was reversed among Hispanics (P = .07). Nevertheless, in both trials, a greater proportion of patients taking iGlarLixi than iGlar reached the composite efficacy endpoints of target A1C without hypoglycemia and target A1C without weight gain, regardless of ethnicity. Conclusion: These results indicate that iGlarLixi is a viable therapeutic option for both Hispanic and NHW patients with T2D, as it is efficacious without a significant increase in hypoglycemia, irrespective of ethnicity. Abbreviations: A1C = glycated hemoglobin; BMI = body mass index; FPG = fasting plasma glucose; FRC = fixed-ratio combination; GLP-1 RA = glucagon-like peptide 1 receptor agonist; HDL-C = high-density-lipoprotein cholesterol; iGlar = insulin glargine; iGlarLixi = insulin glargine + lixisenatide; LDL-C = low-density-lipoprotein cholesterol; NHW = non-Hispanic white; OAD = oral antidiabetes drug; PPG = postprandial glucose; T2D = type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Insulina Glargina/uso terapêutico , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Hemoglobinas Glicadas , Humanos , HipoglicemiantesRESUMO
In the original publication, the text in abstract section under the 'Results' section is incorrectly published as 'higher proportion of patients reached a BeAM value < 55 mg/dL.
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Inflammation is a recognized mechanism underlying the pathogenesis of renal dysfunction in type 1 diabetes. Evidence suggests that genetic factors modulate the expression of inflammatory genes, which may lead to an enhanced predisposition to developing renal complications in patients with diabetes. In this study, we examined 55 genetic variants from 16 human candidate inflammatory genes for associations with renal function expressed as the estimated glomerular filtration rate in 1540 participants from the Genetics of Kidneys in Diabetes study. We observed protective associations between three variants in the CXCL4L1 promoter (rs872914/A, rs941757/G, and rs941758/A) and renal function in patients with type 1 diabetes. In reporter gene assays, all three variants increased CXCL4L1 promoter activity in HEK293 cells stimulated with IL-1 and TNF-α. We performed overexpression and knockdown experiments in primary human mesangial cells to examine the glucose-mediated regulation of endogenous CXCL4L1 gene expression and signaling pathways. The mRNA and protein levels of CXCL4L1 increased in response to high glucose (30 mM) treatment. Overexpression of CXCL4L1 increased the endogenous expression of SMAD7 and IκBα, which are key inhibitory factors in renal inflammation. Knockdown of CXCL4L1 expression also resulted in reduced levels of SMAD7 and IκBα. Our findings suggest that CXCL4L1 promoter variants may protect against the development of renal inflammation in diabetes by increasing CXCL4L1 expression, which in turn activates the anti-inflammatory SMAD7 and IκBα factors in mesangial cells.
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Diabetes Mellitus Tipo 1/genética , Inflamação/genética , Fator Plaquetário 4/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adulto , Idoso , Feminino , Expressão Gênica , Técnicas de Genotipagem , Células HEK293 , Humanos , Interleucina-1/farmacologia , Rim/fisiopatologia , Masculino , Células Mesangiais/metabolismo , Pessoa de Meia-Idade , Inibidor de NF-kappaB alfa/metabolismo , Transdução de Sinais , Proteína Smad7/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. METHODS: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10-20 µg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. FINDINGS: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was -1·69% (95% CI -11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, -21·10% (-42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and -39·18% (-68·53 to -9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741-1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. INTERPRETATION: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. FUNDING: Sanofi.
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Síndrome Coronariana Aguda/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias/prevenção & controle , Peptídeos/uso terapêutico , Albuminúria/complicações , Albuminúria/prevenção & controle , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/complicações , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
INTRODUCTION: A difference of ≥ 50-55 mg/dL between bedtime and morning glucose (BeAM) values in patients with type 2 diabetes (T2D) on basal insulin is an indicator of poor postprandial glucose control. This analysis compared the effect of treatment with a fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) vs insulin glargine (iGlar) on BeAM values, and evaluated the impact of BeAM values on glycemic and safety endpoints. METHODS: In this post hoc analysis of 517 participants from the LixiLan-L trial, change in BeAM values and composite efficacy and safety endpoints stratified by BeAM value < 55 mg/dL or ≥ 55 mg/dL were evaluated in patients with T2D uncontrolled on basal insulin randomized to iGlarLixi or iGlar over 30 weeks (LixiLan-L). RESULTS: Greater reductions in BeAM values were seen with iGlarLixi vs iGlar, and a higher proportion of patients reached a BeAM value < 55 mg/dL in the iGlarLixi arm. A BeAM value < 55 mg/dL was associated with improved glycemic control, lower risk of hypoglycemia, and a greater proportion of patients achieving glycemic targets without hypoglycemia or weight gain. Greater reductions in BeAM values were seen with iGlarLixi vs iGlar, irrespective of stratification by glycated hemoglobin A1c or glycemic endpoints. CONCLUSIONS: Greater reductions in bedtime-to-morning glucose differential, or BeAM, were observed with iGlarLixi vs iGlar in patients with T2D uncontrolled on basal insulin, reflecting better overall control of both fasting and prandial glucose and more appropriate matching of therapy to physiologic needs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02058160. FUNDING: Sanofi US, Inc.
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OBJECTIVE: The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone, and glyoxal hydroimidazolone) and two OP (2-aminoadipic acid and methionine sulfoxide [MetSO]) were measured at baseline in two intensive glucose-lowering studies: 1) a subcohort of the Veterans Affairs Diabetes Trial (VADT) (n = 445) and 2) a nested case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (n = 271). RESULTS: Increased levels of several AGE and OP were associated with older age, decreased kidney function, previous CVD, and longer diabetes duration, but not with hemoglobin A1c. In the VADT, increased risk of incident CVD events (n = 107) was associated with lower MetSO after adjusting for age, race/ethnicity, sex, prior CVD event, kidney function, treatment assignment, and diabetes duration (hazard ratio [HR] 0.53; 95% CI 0.28-0.99; P = 0.047). Individuals with both low MetSO and high 3-deoxyglucosone hydroimidazolone concentrations were at highest risk for CVD (HR 1.70; P = 0.01). In the ACCORD study, those with incident CVD events (n = 136) had lower MetSO (by 14%; P = 0.007) and higher glyoxal hydroimidazolone and carboxymethyl lysine (by 18% and 15%, respectively; P = 0.04 for both); however, only the difference in MetSO remained significant after adjustment for prior CVD event (P = 0.002). CONCLUSIONS: Lower levels of MetSO and higher levels of select AGE are associated with increased incident CVD and may help account for the limited benefit of intensive glucose lowering in type 2 diabetes.
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Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Produtos Finais de Glicação Avançada/sangue , Ácido 2-Aminoadípico/sangue , Idoso , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Estudos de Casos e Controles , Colesterol/sangue , Estudos de Coortes , Desoxiglucose/análogos & derivados , Desoxiglucose/sangue , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Humanos , Imidazóis/sangue , Incidência , Lisina/análogos & derivados , Lisina/sangue , Masculino , Metionina/análogos & derivados , Metionina/sangue , Pessoa de Meia-Idade , Oxirredução , Aldeído Pirúvico/sangue , Fatores de Risco , Triglicerídeos/sangueRESUMO
OBJECTIVE: To determine whether plasma levels of advanced glycation end products and oxidation products play a role in the development of atherosclerosis in patients with type 2 diabetes (T2D) over nearly 10 years of the VA Diabetes Trial and Follow-up Study. RESEARCH DESIGN AND METHODS: Baseline plasma levels of methylglyoxal hydroimidazolone, Nε-carboxymethyl lysine, Nε-carboxyethyl lysine (CEL), 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone (G-H1), 2-aminoadipic acid (2-AAA), and methionine sulfoxide were measured in a total of 411 participants, who underwent ultrasound assessment of carotid intima-media thickness (CIMT), and computed tomography scanning of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) after an average of 10 years of follow-up. RESULTS: In risk factor-adjusted multivariable regression models, G-H1 was associated with the extent of CIMT and CAC. In addition, 2-AAA was strongly associated with the extent of CAC, and CEL was strongly associated with the extent of AAC. The combination of specific advanced glycation end products and oxidation products (G-H1 and 2-AAA) was strongly associated with all measures of subclinical atherosclerosis. CONCLUSIONS: Specific advanced glycation end products and metabolic oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the "negative metabolic memory" of macrovascular complications in people with long-standing T2D.
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Aterosclerose/sangue , Diabetes Mellitus Tipo 2/sangue , Produtos Finais de Glicação Avançada/sangue , Idoso , Aterosclerose/diagnóstico , Glicemia/metabolismo , Espessura Intima-Media Carotídea , Colesterol/sangue , Desoxiglucose/análogos & derivados , Desoxiglucose/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Seguimentos , Humanos , Imidazóis/sangue , Lisina/análogos & derivados , Lisina/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução , Aldeído Pirúvico/sangue , Triglicerídeos/sangueRESUMO
OBJECTIVES: Prediabetes is a major epidemic and is associated with adverse cardio-cerebrovascular outcomes. Early identification of patients who will develop rapid progression of atherosclerosis could be beneficial for improved risk stratification. In this paper, we investigate important factors impacting the prediction, using several machine learning methods, of rapid progression of carotid intima-media thickness in impaired glucose tolerance (IGT) participants. METHODS: In the Actos Now for Prevention of Diabetes (ACT NOW) study, 382 participants with IGT underwent carotid intima-media thickness (CIMT) ultrasound evaluation at baseline and at 15-18 months, and were divided into rapid progressors (RP, n = 39, 58 ± 17.5 µM change) and non-rapid progressors (NRP, n = 343, 5.8 ± 20 µM change, p < 0.001 versus RP). To deal with complex multi-modal data consisting of demographic, clinical, and laboratory variables, we propose a general data-driven framework to investigate the ACT NOW dataset. In particular, we first employed a Fisher Score-based feature selection method to identify the most effective variables and then proposed a probabilistic Bayes-based learning method for the prediction. Comparison of the methods and factors was conducted using area under the receiver operating characteristic curve (AUC) analyses and Brier score. RESULTS: The experimental results show that the proposed learning methods performed well in identifying or predicting RP. Among the methods, the performance of Naïve Bayes was the best (AUC 0.797, Brier score 0.085) compared to multilayer perceptron (0.729, 0.086) and random forest (0.642, 0.10). The results also show that feature selection has a significant positive impact on the data prediction performance. CONCLUSIONS: By dealing with multi-modal data, the proposed learning methods show effectiveness in predicting prediabetics at risk for rapid atherosclerosis progression. The proposed framework demonstrated utility in outcome prediction in a typical multidimensional clinical dataset with a relatively small number of subjects, extending the potential utility of machine learning approaches beyond extremely large-scale datasets.
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OBJECTIVE: To determine whether a link exists between serious hypoglycemia and progression of atherosclerosis in a substudy of the Veterans Affairs Diabetes Trial (VADT) and to examine whether glycemic control during the VADT modified the association between serious hypoglycemia and coronary artery calcium (CAC) progression. RESEARCH DESIGN AND METHODS: Serious hypoglycemia was defined as severe episodes with loss of consciousness or requiring assistance or documented glucose <50 mg/dL. Progression of CAC was determined in 197 participants with baseline and follow-up computed tomography scans. RESULTS: During an average follow-up of 4.5 years between scans, 97 participants reported severe hypoglycemia (n = 23) or glucose <50 mg/dL (n = 74). Serious hypoglycemia occurred more frequently in the intensive therapy group than in the standard treatment group (74% vs. 21%, P < 0.01). Serious hypoglycemia was not associated with progression of CAC in the entire cohort, but the interaction between serious hypoglycemia and treatment was significant (P < 0.01). Participants with serious hypoglycemia in the standard therapy group, but not in the intensive therapy group, had â¼50% greater progression of CAC than those without serious hypoglycemia (median 11.15 vs. 5.4 mm(3), P = 0.02). Adjustment for all baseline differences, including CAC, or time-varying risk factors during the trial, did not change the results. Examining the effect of serious hypoglycemia by on-trial HbA1c levels (cutoff 7.5%) yielded similar results. In addition, a dose-response relationship was found between serious hypoglycemia and CAC progression in the standard therapy group only. CONCLUSIONS: Despite a higher frequency of serious hypoglycemia in the intensive therapy group, serious hypoglycemia was associated with progression of CAC in only the standard therapy group.
Assuntos
Aterosclerose/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/diagnóstico por imagem , Hipoglicemia/sangue , Calcificação Vascular/diagnóstico por imagem , Idoso , Aterosclerose/sangue , Aterosclerose/etiologia , Glicemia/análise , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/etiologia , Progressão da Doença , Feminino , Humanos , Hipoglicemia/etiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , VeteranosRESUMO
OBJECTIVE: To examine the effect of intensive glycemic control on cardiovascular disease events (CVD) among the major race/ethnic groups in a post-hoc analysis of the VADT. MATERIALS AND METHODS: Participants included 1111 non-Hispanic Whites, 307 Hispanics and 306 non-Hispanic Blacks randomized to intensive or standard glucose treatment in VADT. Multivariable Cox proportional hazards models were constructed to assess the effect of intensive glucose treatment on CVD events among race/ethnic groups. RESULTS: Mean age was 60.4 years and median follow-up was 5.6 years. By design, modifiable risk factors were managed equally well in both treatment arms and only differed modestly between race/ethnic groups. HbA(1c) decreased significantly from baseline with intensive glucose treatment in each race/ethnic group, with a trend for a greater response in Hispanics (P=0.02 for overall comparison between groups). Intensive glucose treatment was associated with reduced risk of CVD events for Hispanics but not for others (hazard ratios ranged from 0.54 to 0.75 for Hispanics whereas they were consistently close to 1 for others). Sensitivity analyses with different definitions of race/ethnicity or limited to individuals free of previous known CVD yielded similar results. CONCLUSIONS: The results of these analyses support the hypothesis that race/ethnicity is worthy of consideration when tailoring intensive treatment for individuals with long-standing type 2 diabetes. However, additional studies are needed to confirm the findings of this post-hoc analysis.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/terapia , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , Hiperglicemia/prevenção & controle , Medicina de Precisão , Negro ou Afro-Americano , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etnologia , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/complicações , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etnologia , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/etnologia , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Hispânico ou Latino , Hospitais de Veteranos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Estados Unidos/epidemiologia , População BrancaRESUMO
OBJECTIVE: Intensive glucose-lowering therapy (INT) did not reduce macrovascular events in the recent randomized trials, possibly because it did not improve or worsen other traditional or novel cardiovascular risk factors. RESEARCH DESIGN AND METHODS: Standard plasma lipids, cholesterol content of lipoprotein subfractions, and plasma inflammatory and prothrombotic markers were determined in a subgroup of the Veterans Affairs Diabetes Trial (VADT) participants (n = 266) at baseline and after 9 months of INT or standard therapy. RESULTS: INT lowered glycated hemoglobin (by a median of 2% vs. a median of 0.7% by standard treatment; P < 0.0001); increased BMI (4 vs. 1%; P < 0.001), total HDL (9 vs. 4%; P < 0.05), HDL2 (14 vs. 0%; P = 0.009), LDL2 (36 vs. 1%; P < 0.0001), and plasma adiponectin (130 vs. 80%; P < 0.01); and reduced triglycerides (-13 vs. -4%; P = 0.02) and small, dense LDL4 (-39 vs. -13%; P < 0.001), but had no effect on levels of plasma apolipoproteins B-100 and B-48, C-reactive protein, interleukin-6, lipoprotein-associated phospholipase A2, myeloperoxidase, fibrinogen, and plasminogen activator inhibitor 1. Incident macrovascular events were associated with baseline interleukin-6 (hazard ratio per each quartile increase 1.33 [95% CI 1.06-1.66]), total LDL (1.25 [1.01-1.55]), apolipoprotein B-100 (1.29 [1.01-1.65]), and fibrinogen (1.26 [1.01-1.57]) but not changes in any cardiovascular risk factors at 9 months. CONCLUSIONS: INT was associated with improved adiponectin, lipid levels, and a favorable shift in LDL and HDL subfractions after 9 months. These data suggest that the failure of INT to lower cardiovascular outcomes occurred despite generally favorable changes in standard and novel risk factors early in the study.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Lipoproteínas/sangue , Biomarcadores , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/administração & dosagem , Interleucina-6 , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Fatores de Risco , Rosiglitazona , Tiazolidinedionas/administração & dosagemRESUMO
OBJECTIVE: To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes. METHODS AND RESULTS: CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76×10(-3) mm/year; 95% CI: 2.39×10(-3)-7.14×10(-3) mm/year) compared with placebo (9.69×10(-3) mm/year; 95% CI: 7.24×10(-3)-12.15×10(-3) mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA(1c), fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment. CONCLUSIONS: Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
Assuntos
Doenças das Artérias Carótidas/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Hipoglicemiantes/uso terapêutico , Estado Pré-Diabético/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/etiologia , Espessura Intima-Media Carotídea , Distribuição de Qui-Quadrado , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiologia , Progressão da Doença , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pioglitazona , Inibidor 1 de Ativador de Plasminogênio/sangue , Estado Pré-Diabético/sangue , Estado Pré-Diabético/complicações , Estado Pré-Diabético/diagnóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVE: To determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS: Progression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM. RESULTS: After adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.2 ± 0.5 mm(3) vs. 4.2 ± 1.1 mm(3); P < 0.01). AAC progression was in general not significantly increased with more frequent statin use; in a subgroup of participants initially not receiving statins, however, progression of both CAC and AAC was significantly increased in frequent statin users. CONCLUSIONS: More frequent statin use is associated with accelerated CAC in T2DM patients with advanced atherosclerosis.
Assuntos
Doenças da Aorta/induzido quimicamente , Doença da Artéria Coronariana/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Calcificação Vascular/induzido quimicamente , Idoso , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
IL-6 is believed to mediate the elevation in plasma TG and VLDL lipids in patients with sepsis. Previous studies of lipoprotein density fractions do not reveal the extent to which cytokines change the immunochemically distinct TG-rich (LpB:C, LpB:C:E, LpAII:B:C:D:E) and cholesterol-rich (LpB, LpB:E) apoB-containing subclasses present in VLDL. Therefore, we have directly measured these subclasses following their isolation by sequential immunoprecipitation in seven healthy male subjects during a 3-h infusion with recombinant human (rh) IL-6. Though plasma TG and apoB-containing particle number were unchanged by IL-6, the distribution of TG-rich subclasses was significantly altered. Compared to baseline values, LpB:E + LpB:C:E increased significantly at 0.5 h (p < 0.02) and were higher than saline-infused controls at 0.5 and 1 h (p < 0.05). At 0.5 h LpAII:B:C:D:E reciprocally declined from baseline (p < 0.01). While the pattern of change for total apoB showed an overall decline (p < 0.05), these changes in LpB:E + LpB:C:E and LpAII:B:C:D:E in IL-6 subjects differed from controls (p < 0.05; p < 0.01, respectively). These findings indicate that physiologic concentrations of IL-6 rapidly and selectively regulate the transport of apoB particles that contain apoE. Since apoE has immunomodulatory and host defense functions, these changes may be a previously unrecognized early step in the innate immune response.