Low HbA1c and mortality: causation and confounding

Rutter, Martin K.

doi:10.1007/s00125-012-2620-3

Cited by 24 publications

(26 citation statements)

References 31 publications

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“…Findings compared with previous studies Recent trials have found that intensive glucose control is associated with increased risk of cardiovascular death in younger patients [8] and observational studies have generally demonstrated Ushaped relationships between levels of HbA 1c in diabetic patients and death [28,29], possibly attributable to residual confounding through unmeasured variables [12]. In our study we adjusted for several important confounders, including comorbidities such as heart failure, chronic obstructive airways disease and chronic kidney disease.…”

Section: Discussionmentioning

confidence: 80%

“…Similarly, BP control below 130/ 80 mmHg was recently found not to reduce all-cause mortality in newly diagnosed diabetes patients [11]. Other studies demonstrated a U-shaped relationship between HbA 1c levels and all-cause mortality, which is possibly attributable to residual confounding through unmeasured variables [12]. For example, patients in the later stages of cancer often have low plasma glucose levels, where the elevated risks of adverse outcomes are due to the cancer not the hypoglycaemia.…”

Section: Introductionmentioning

confidence: 97%

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Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

et al. 2014

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Aims/hypothesis We aimed to describe the shape of observed relationships between risk factor levels and clinically important outcomes in type 2 diabetes after adjusting for multiple confounders.Methods We used retrospective longitudinal data on 246,544 adults with type 2 diabetes from 600 practices in the Clinical Practice Research Datalink, 2006Datalink, -2012 Proportional hazards regression models quantified the risks of mortality and microvascular or macrovascular events associated with four modifiable biological variables (HbA 1c , systolic BP, diastolic BP and total cholesterol), while controlling for important patient and practice covariates. Results U-shaped relationships were observed between allcause mortality and levels of the four biometric risk factors. Lowest risks were associated with HbA 1c 7.25-7.75% (56-61 mmol/mol), total cholesterol 3.5-4.5 mmol/l, systolic BP 135-145 mmHg and diastolic BP 82.5-87.5 mmHg. Coronary and stroke mortality related to the four risk factors in a positive, curvilinear way, with the exception of systolic BP, which related to deaths in a U-shape. Macrovascular events showed a positive and curvilinear relationship with HbA 1c but a U-shaped relationship with total cholesterol and systolic BP. Microvascular events related to the four risk factors in a curvilinear way: positive for HbA 1c and systolic BP but negative for cholesterol and diastolic BP. Conclusions/interpretation We identified several relationships that support a call for major changes to clinical practice. Most importantly, our results support trial data indicating that normalisation of glucose and BP can lead to poorer outcomes. This makes a strong case for target ranges for these risk factors rather than target levels.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 97%

Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

et al. 2014

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“…Based on the squared difference of the measurements to their average value, the approach would seem to amplify large differences. The difficulty in the definition and interpretation of HbA 1c variability has been noted by several authors [15,16]. Our approach provides a partial but imperfect solution to these problems; while accounting for the length of time between measurements, the variance of our statistic may be higher with widely spaced measurements.…”

Section: Discussionmentioning

confidence: 98%

“…The RIACE study group found no association between HbA 1c variability and myocardial infarction or stroke [13] Here, CVD was defined more widely, including, for example, myocardial infarction, heart failure and non-fatal ischaemic stroke [10]. Interestingly, the recent literature is quite inconsistent about the relationship between the effect of low HbA 1c and the risk of mortality or CVD [15]. Various studies demonstrated a consistent positive linear relationship between HbA 1c and the risk of mortality or CVD [29,30].…”

Section: Discussionmentioning

confidence: 99%

“…The possible risks of HbA 1c variability in different subgroups are still not well understood and are intensively discussed. This discussion has even cast doubt on previous findings, suggesting possible statistical bias in the methods [15,16]. There remains, therefore, some uncertainty as to the importance of HbA 1c variability as a concept distinct from either the absolute HbA 1c value or from a one-off rapid decrease to a target value.…”

Section: Introductionmentioning

confidence: 96%

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Association of the average rate of change in HbA1c with severe adverse events: a longitudinal evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus

et al. 2015

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Aims/hypothesis In patients with type 2 diabetes mellitus, the effects of HbA 1c variability on macrovascular events remain uncertain. The present investigation evaluates the association of HbA 1c variability with non-fatal cardiovascular events, emergency admissions and episodes of severe hypoglycaemia in a cohort of patients newly started on insulin therapy. Methods HbA 1c variability was defined as the rate of change in values between observations. The medical records of 406,356 patients enrolled in a disease management programme for type 2 diabetes mellitus were analysed to identify a cohort of 13,777 patients with observed transition to insulin therapy. The cohort was observed for a period of at least 5 years. Cox regression models were applied to quantify the association of HbA 1c variability with the events of interest. Results The models reveal a significant non-linear association between HbA 1c variability and the risk of experiencing myocardial infarction, stroke and hypoglycaemia. The lowest risk is seen with a variability of approximately 0.5% (5.5 mmol/ mol) per quarter. Using Cox models to predict survival curves for the cohort with hypothetical HbA 1c variability of 0.5% (5.5 mmol/mol) and 1.5% (16.4 mmol/mol) per quarter, the proportion experiencing myocardial infarction within 2 years increases significantly from 1% to 10%. The proportion experiencing stroke increases from 1% to 29%, hypoglycaemia from 2% to 24% and the risk of emergency admission from 2% to 21%. Conclusions/interpretation In patients newly started on insulin therapy, rapid and higher HbA 1c variability is associated with an increased risk of myocardial infarction, stroke, severe hypoglycaemia and emergency admission.

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Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

Angelantonio

Gao

Khan

et al. 2014

JAMA

195

121

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IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294 998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5%to <7.5%), and high (≥7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20 840 incident fatal and nonfatal CVD outcomes (13 237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (−0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

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Low HbA1c and mortality: causation and confounding

Abstract: This commentary provides an overview of the clinically important data linking low or lowered HbA 1c to increased total and CVD mortality in the general population, and in patients with diabetes. This sets the scene for a contribution in this issue of Diabetologia by Andersson et al

Cited by 24 publications

References 31 publications

Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

Association of the average rate of change in HbA1c with severe adverse events: a longitudinal evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

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