Abstract
Aims/hypothesisIntensive glucose control reduces the risk of vascular complications while increasing the risk of severe hypoglycaemia at a group level. We sought to estimate individual beneficial and adverse effects of intensive glucose control in patients with type 2 diabetes.MethodsWe performed a post hoc analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, a randomised controlled trial evaluating standard vs intensive glucose control (HbA1c target ≤6.5% [48 mmol/mol]). In 11,140 participants, we estimated the individual 5 year absolute risk reduction (ARR) for the composite outcome of major micro- and macrovascular events and absolute risk increase (ARI) for severe hypoglycaemia for intensive vs standard glucose control. Predictions were based on competing risks models including clinical characteristics and randomised treatment.ResultsBased on these models, 76% of patients had a substantial estimated 5 year ARR for major vascular events (>1%, 5 year number-needed-to-benefit [NNTB5] <100) and 1% had a small ARR (<0.5%, NNTB5 >200). Similarly, 36% of patients had a substantial estimated ARI for severe hypoglycaemia (5 year number-needed-to-harm [NNTH5] <100) and 29% had a small ARI (NNTH5 >200). When assigning similar or half the weight to severe hypoglycaemia compared with a major vascular event, net benefit was positive in 85% or 99% of patients, respectively. Limiting intensive treatment to the 85% patient subgroup had no significant effect on the overall incidence of major vascular events and severe hypoglycaemia compared with treating all patients.Conclusions/interpretationTaking account of the effects of intensive glucose control on major micro- and macrovascular events and severe hypoglycaemia for individual patients, the estimated net benefit was positive in the majority of the participants in the ADVANCE trial. The estimated individual effects can inform treatment decisions once individual weights assigned to positive and adverse effects have been specified.Trial registration:ClinicalTrials.gov NCT00145925Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4082-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Type 2 diabetes mellitus is a growing worldwide health problem, with 592 million people predicted to be living with diabetes by 2035 [1]
Model derivation and performance The baseline characteristics of the ADVANCE participants are shown in Table 1 and the use of glucose-lowering drugs in the electronic supplementary material (ESM) Table 1
Where S0(5) = 0.9845 and A is the sum, over all variables in the model, of the patient’s specific value × the corresponding coefficient aCoefficients were penalised by a shrinkage factor of 0.886 to increase external validity, whereas unbiased HRs and statistics were derived from an unpenalised Fine and Gray model bNeeds to be combined with the interaction term to estimate effect of intensive glucose control at specific HbA1c value (e.g. coefficient = −0.6808 + HbA1c (%) × 0.1622)
Summary
Type 2 diabetes mellitus is a growing worldwide health problem, with 592 million people predicted to be living with diabetes by 2035 [1]. Observational studies have shown a close relationship between hyperglycaemia and the risk of vascular complications [2,3,4]. Randomised trials have demonstrated beneficial effects of intensive glucose control on the incidence of microvascular diseases, such as retinopathy and nephropathy [5, 6]. The reduction in risk of macrovascular events has been modest in the short and medium term and may take more time to accrue [7,8,9]. Intensive glucose control is associated with disadvantages, such as an approximately doubled risk of severe hypoglycaemia depending on the glucose-lowering treatment being received [6, 10]. In turn, associated with a nearly threefold increased risk of premature death, this association may not be causal [11]
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