The hemoglobin glycation index is not an independent predictor of the risk of microvascular complications in the Diabetes Control and Complications Trial

W badaniu DCCT wykazano, że intensywne leczenie mające na celu poprawę wyrównania glikemii znacząco zmniejszyło ryzyko powikłań cukrzycowych w porównaniu z konwencjonalnym leczeniem. Najistotniejszym wyznacznikiem ryzyka był wywiad dotyczący stężenia glukozy we krwi. Ostatnio McCarter i wsp. (Diabetes Care 2004; 27: 1259-1264) przedstawili analizę ogólnie dostępnych danych z DCCT dotyczących indeksu glikacji (HGI), obliczonego jako różnica między obserwowanym stężeniem HbA1c a stężeniem przewidywanym na podstawie wartości glikemii. W tej analizie wykazano, że wartość HGI była znamiennym czynnikiem predykcyjnym progresji retinopatii i nefropatii w DCCT, co autorzy uznali za poparcie tezy, że biologiczna skłonność do glikacji, tak zwana biologiczna wariacja glikacji, jest kolejnym mechanizmem, który odpowiada za ryzyko powstawania powikłań. Jednak w niniejszej pracy skrytykowano te analizy i wnioski, ponieważ z zasad statystyki wynika, że HGI musi być dodatnio skorelowany ze stężeniem HbA1c i dlatego może je zastępować. Autorzy przedstawiają statystyczne własności HGI w celu udokumentowania jego wysokiej korelacji z HBA1c. Następnie powtarzają analizę McCartera i wsp. z użyciem zarówno HGI, jak i HbA1c. W analizie wykazano ostatecznie, że HGI nie jest niezależnym czynnikiem ryzyka powikłań mikronaczyniowych i że stężenie HbA1c całkowicie tłumaczy wpływ indeksu glikacji na to ryzyko. Nie należy używać HGI do oceny ryzyka powikłań ani uzależniać od niego decyzji terapeutycznych.The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy aimed at improved glucose control markedly reduced the risk of diabetes complications compared with conventional therapy. The principal determinant of risk was the history of glycemia. Recently, McCarter et al. (Diabetes Care 2004; 27: 1259–1264) have presented analyses of the publicly available DCCT data using their hemoglobin glycation index (HGI), which is computed as the difference between the observed HbA1c (A1C) and that predicted from the level of blood glucose. In their analyses, the HGI level was a significant predictor of progression of retinopathy and nephropathy in the DCCT, which the authors claimed to support the hypothesis that the biological propensity for glycation, socalled biological variation in glycation, is another mechanism that determines risk of complications. However, we have criticized these analyses and conclusions because, from statistical principles, the glycation index must be positively correlated with the A1C level and thus may simply be a surrogate for A1C. Herein, we present the statistical properties of the glycation index to document its high correlation with A1C. We then replicate the analyses of McCarter et al. using both the HGI and the A1C together. Analyses show conclusively that the glycation index is not an independent risk factor for microvascular complications and that the effect of the glycation index on risk is wholly explained by the associated level of A1C. The HGI should not be used to estimate risk of complications or to guide therapy

Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes

BACKGROUND: We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7-9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15-16 (n = 142). METHODS: Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses. RESULTS: Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p \u3c 0.05) and CAC \u3e0 (p = 0.39), but not with CAC score100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P \u3c 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p \u3c 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p \u3c 0.05), and highly with CML (p \u3c 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane, CONCLUSIONS: In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation. TRIAL REGISTRATION: Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov

Haptoglobin Genotype and the Rate of Renal Function Decline in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

Many patients with type 1 diabetes develop renal disease despite moderately good metabolic control, suggesting other risk factors may play a role. Recent evidence suggests that the haptoglobin (HP) 2-2 genotype, which codes for a protein with reduced antioxidant activity, may predict renal function decline in type 1 diabetes. We examined this hypothesis in 1,303 Caucasian participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. HP genotype was determined by polyacrylamide gel electrophoresis. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and albumin excretion based on timed urine samples. Participants were followed up for a mean of 22 years. HP genotype was significantly associated with the development of sustained estimated glomerular filtration rate (GFR) \u3c60 mL/min/1.73 m2and with end-stage renal disease (ESRD), with HP 2-2 having greater risk than HP 2-1 and 1-1. No association was seen with albuminuria. Although there was no treatment group interaction, the associations were only significant in the conventional treatment group, where events rates were much higher. We conclude that the HP genotype is significantly associated with the development of reduced GFR and ESRD in the DCCT/EDIC study

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy

Nine-Year Effects of 3.7 Years of Intensive Glycemic Control on Cardiovascular Outcomes

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, ∼4 years of intensive versus standard glycemic control in participants with type 2 diabetes and other cardiovascular risk factors had a neutral effect on the composite cardiovascular outcome, increased cardiovascular and total mortality, and reduced nonfatal myocardial infarction. Effects of the intervention during prolonged follow-up were analyzed

Insulin Dose and Cardiovascular Mortality in the ACCORD Trial

In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality

Plasma advanced glycation end products and the subsequent risk of microvascular complications in type 1 diabetes in the DCCT/EDIC

INTRODUCTION: To assess impact of glycemic control on plasma protein-bound advanced glycation end products (pAGEs) and their association with subsequent microvascular disease. RESEARCH DESIGN AND METHODS: Eleven pAGEs were measured by liquid chromatography-mass spectrometry in banked plasma from 466 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study at three time points (TPs): DCCT year 4 (TP1) and year 8 (TP2) and EDIC year 5/6 (TP3). Correlation coefficients assessed cross-sectional associations, and Cox proportional hazards models assessed associations with subsequent risk of microvascular complications through EDIC year 24. RESULTS: Glucose-derived glycation products fructose-lysine (FL), glucosepane (GSPN) and carboxymethyl-lysine (CML) decreased with intensive glycemic control at both TP1 and TP2 (p\u3c0.0001) but were similar at TP3, and correlated with hemoglobin A1c (HbA1c). At TP1, the markers were associated with the subsequent risk of several microvascular outcomes. These associations did not remain significant after adjustment for HbA1c, except methionine sulfoxide (MetSOX), which remained associated with diabetic kidney disease. In unadjusted models using all 3 TPs, glucose-derived pAGEs were associated with subsequent risk of proliferative diabetic retinopathy (PDR, p\u3c0.003), clinically significant macular edema (CSME, p\u3c0.015) and confirmed clinical neuropathy (CCN, p\u3c0.018, except CML, not significant (NS)). Adjusted for age, sex, body mass index, diabetes duration and mean updated HbA1c, the associations remained significant for PDR (FL: p\u3c0.002, GSPN: p≤0.02, CML: p\u3c0.003, pentosidine: p\u3c0.02), CMSE (CML: p\u3c0.03), albuminuria (FL: p\u3c0.02, CML: p\u3c0.03) and CCN (FL: p\u3c0.005, GSPN : p\u3c0.003). CONCLUSIONS: pAGEs at TP1 are not superior to HbA1c for risk prediction, but glucose-derived pAGEs at three TPs and MetSOX remain robustly associated with progression of microvascular complications in type 1 diabetes even after adjustment for HbA1c and other factors