Elsevier

The Lancet

Volume 375, Issue 9713, 6–12 February 2010, Pages 481-489
The Lancet

Articles
Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study

https://doi.org/10.1016/S0140-6736(09)61969-3Get rights and content

Summary

Background

Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a function of HbA1c in people with type 2 diabetes.

Methods

Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly.

Findings

For combined cohorts, compared with the glycated haemoglobin (HbA1c) decile with the lowest hazard (median HbA1c 7·5%, IQR 7·5–7·6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA1c decile (6·4%, 6·1–6·6) was 1·52 (95% CI 1·32–1·76), and in the highest HbA1c decile (median 10·5%, IQR 10·1–11·2%) was 1·79 (95% CI 1·56–2·06). Results showed a general U-shaped association, with the lowest HR at an HbA1c of about 7·5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1·49 (95% CI 1·39–1·59).

Interpretation

Low and high mean HbA1c values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value.

Funding

Eli Lilly and Company.

Introduction

The main objective for care of patients with diabetes mellitus is to keep the risk of microvasular and macrovascular complications to a minimum by returning blood pressure, lipid profiles, and glycaemia to normal.1 The specific goal for control of glycaemia is to return glycated haemoglobin (HbA1c) to a normal range, because good glycaemic control is known to reduce risk of long-term microvascular complications in both type 12 and type 2 diabetes.3, 4 Researchers of the ADVANCE trial5 and the ACCORD study6 investigated the effect of targeted type 2 diabetes glycaemic control on macrovascular outcomes in patients with diabetes and microvascular or macrovascular disease. Both studies failed to show that achievement of good glycaemic control was associated with reduction of cardiovascular risk.

Reports of potentially raised mortality rates associated with intensive glycaemic control have triggered discussion about recommendations for treatment of type 2 diabetes, specifically relating to the optimum target for HbA1c. Researchers have suggested that hypoglycaemia contributes to a heightened risk of mortality in patients with diabetes. Because intensive glycaemic control increases risk of hypoglycaemia with some drugs more than with others, assessment of risks associated with the different blood glucose-lowering regimens is important. In two meta-analyses,7, 8 researchers combined data from several important trials5, 6, 9 and concluded that intensive glycaemic control has positive effects on cardiovascular endpoints. However, these meta-studies were constrained by inherent limitations of the clinical trials that were analysed.

In this retrospective cohort study, our aim was to assess the association between all-cause mortality and HbA1c in patients with type 2 diabetes in a primary-care setting, and establish whether any evident association was independent of the diabetes treatment regimen.

Section snippets

Sample selection

We obtained data from routine general practice in the UK from a proprietary health data resource: the General Practice Research Database (GPRD).10, 11 GPRD was established in 1987, and contains data derived from computerised records. A detailed description of GPRD is available elsewhere.12 GPRD data are gathered in a non-interventional way from the daily record keeping of general practitioners. Records are anonymised at the time that they are obtained. They contain the following information:

Results

We identified 27 965 patients who met the criteria for cohort 1. Table 1 shows baseline characteristics of this cohort and provides baseline characteristics by HbA1c decile. Baseline mean HbA1c (before treatment escalation index date) was 9·0% (SD 1·5). The age and proportion of patients with a previous diagnosis of large-vessel disease were highest in the group with the lowest post-index mean HbA1c.

We identified 20 005 patients who met criteria for cohort 2. Table 2 shows baseline

Discussion

We have shown that an HbA1c of approximately 7·5% was associated with lowest all-cause mortality and lowest progression to large-vessel disease events. An increase or decrease from this mean HbA1c value was associated with heightened risk of adverse outcomes. The U-shaped pattern of risk association was sufficiently similar in the two treatment cohorts to suggest that risk of mortality with respect to HbA1c was independent of treatment regimen. Furthermore, we noted that mortality risk between

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