Estimation of individual beneficial and adverse effects of intensive glucose control for patients with type 2 diabetes

Abstract

Aims/hypothesis: Intensive 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.

Methods: We 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.

Results: Based 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/interpretation: Taking 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 NCT00145925.

Keywords: Glycaemic target; Hypoglycaemia; Net benefit; Personalised medicine; Type 2 diabetes; Vascular complications.

Conflict of interest statement

Duality of interest

JC has received research grants from Servier, administered through the University of Sydney, as Principal Investigator for ADVANCE and ADVANCE-ON, and has also received honoraria from Servier for speaking about ADVANCE at scientific meetings. MW is a consultant for Novartis and Amgen. SZ received fees for serving Dohme, Bristol-Myers Squibb–AstraZeneca, Sanofi-Aventis, Novo Nordisk and Amgen, lecture fees from Servier, Merck Sharp and Dohme, and Bristol-Myers Squibb–AstraZeneca, and fees to her institution for research contract work with Bristol-Myers Squibb–AstraZeneca. SHa received lecture fees from Servier, Takeda and Novartis. SHe received fees for serving on advisory boards from Eli Lilly, Novo Nordisk and Takeda, and lecture fees from Eli Lilly, Novo Nordisk, Takeda and Boehringer Ingelheim. GM received lecture fees from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novartis, Menarini International, Recordati, Servier and Takeda. MM received personal fees from Novo Nordisk, Sanofi, Eli Lilly, Merck Sharp and Dohme, Abbott, Novartis, Servier and Astra-Zeneca, and grant support from Novo Nordisk, Sanofi, Eli Lilly, Merck Sharp and Dohme, and Novartis. NP received honoraria from Servier, Takeda, Menarini and Pfizer, and grant support from Servier and Pfizer. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Contribution statement

JvdL designed and carried out the data analyses, interpreted the results and drafted the manuscript. FLJV, MW, SZ, YG, DEG and JC contributed to the acquisition of data, designed the data analyses, interpreted the results and revised the manuscript critically for important intellectual content. SHa, SHe, GM, MM and NP contributed to the acquisition of data and revised the manuscript critically for important intellectual content. The current study was designed, conducted, interpreted, and reported independently of the study sponsor. MW and JC are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data. All authors gave their final approval of this version of the manuscript.

Figures

Fig. 1

Calibration plots. Predicted vs observed 5 year risk of (a) major vascular events and (b) severe hypoglycaemia in ADVANCE participants (N = 11,140). Data is presented as mean ± 95% CI

Fig. 2

Graphical representation of the interaction between glucose-lowering treatment and baseline HbA1c on the risk of severe hypoglycaemia. HbA1c is expressed continuously on the x-axis. The y-axis shows the risk of severe hypoglycaemia under standard and intensive glucose control relative to a person with an HbA1c of 7.5% (the mean) on standard glucose control. To convert values for HbA1c in % to mmol/mol, subtract 2.15 and multiply by 10.929. Solid line, standard glucose control with 95% CI; dashed line, intensive glucose control with 95% CI

Fig. 3

Distribution of individual patient treatment effects of intensive glucose control for (a) 5 year ARR for major vascular events and (b) ARI for severe hypoglycaemia, and net treatment effect assigning (c) half the weight or (d) similar weight to severe hypoglycaemia

Fig. 4

Overall effects of selective intensive glucose control treatment on the 5 year incidence of major vascular events and severe hypoglycaemia. The x-axis shows the proportion of patients treated. Patients were ranked according to their estimated net benefit (largest to smallest), e.g. the first 85% of patients had an estimated positive individual net effect. The left y-axis shows the 5 year risk of major vascular events (solid line) and the right y-axis shows the 5 year risk of severe hypoglycaemia (dashed line)

Fig. 5

Overall effect of selective prediction-based treatment. 5 year effect on the incidence of major vascular events (ARR) and 5 year effect on the incidence of severe hypoglycaemia (ARI) compared with treating everyone (dotted line). The ‘prediction-based’ sample comprises patients with a positive estimated net benefit from the intervention group and patients with a null or negative estimated net benefit from the control group. Circle, major vascular events; square, severe hypoglycaemia. Error bars represent 95% CI