P4990Heterogeneity of treatment effects from an intensive lifestyle weight loss intervention on cardiovascular events in patients with type 2 diabetes: data from the Look AHEAD trial
Authors: De Vries T I , Dorresteijn J A N , Van Der Graaf Y , Visseren F L J , Westerink J 
Published: October 2019

Abstract

Background
The Action for Health in Diabetes trial (Look AHEAD) randomized overweight and obese patients with type 2 diabetes to either an intensive lifestyle intervention (ILI) or diabetes support and education (DSE). The trial was stopped early for futility after a median follow-up of 9.6 years due to a lack of effect on cardiovascular disease outcomes, despite beneficial effects on metabolic control and cardiovascular risk factors. Subgroup analyses identified no subgroups based on baseline characteristics with a significant treatment effect. However, traditional simple subgroup analyses have several disadvantages compared to a multivariable risk-based approach to identify heterogeneity of treatment effects (HTE).

Purpose
To explore the possible presence of HTE of an ILI on the occurrence of major cardiovascular events (4-point MACE: nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, and death from cardiovascular causes) in overweight or obese patients with type 2 diabetes mellitus, and to identify patient characteristics associated with treatment.

Methods
In 4,901 patients from Look AHEAD, a ridge penalized Cox regression model to predict treatment effect of ILI versus DSE on the risk of MACE was derived including all possible treatment-by-covariate interaction terms. Next, the ability of the model to predict HTE was confirmed by calculating hazard ratios (HR) and absolute risk change in quartiles of predicted treatment effect, thereby leaving randomization intact. Finally, baseline patient characteristics were compared between quartiles of predicted treatment effect.

Results
During a median follow-up of 9.4 years, 799 events occurred (Fig. 1A). The derived risk model showed good internal calibration, with a C-statistic for discrimination of 0.73 (95% confidence interval [95% CI] 0.71–0.73). The median estimated absolute treatment effect on 10 year risk for MACE with ILI was −1.3% and varied substantially, ranging from −39% to +43% (Fig. 1B). In quartile 1, the quartile with the highest benefit, there was a significant treatment benefit of ILI versus DSE (HR 0.64; 95% CI 0.49–0.83), while there was no effect from treatment in quartiles 2 and 3 (HR 0.81, 95% CI 0.58–1.14, and 1.13, 95% CI 0.80–1.60, respectively), and a detrimental effect in quartile 4 (HR 1.37, 95% CI 1.09–1.73) (Fig. 1C). Patient characteristics most notably associated with higher benefit of ILI were higher age, male sex, higher socio-economic status, no history of cardiovascular disease, no use of insulin, higher blood pressure, lower HbA1c, and the presence of micro-albuminuria but absence of macro-albuminuria.
Figure 1

Conclusion
This post-hoc analysis of the Look AHEAD trial shows evidence of considerable HTE of an intensive lifestyle intervention aimed at weight loss for reducing MACE. Future research into ILI for MACE risk reduction should be specifically aimed at subgroups of patients with a high likelihood of treatment benefit.

Acknowledgement/Funding
None