Physicians' Academy for Cardiovascular Education

Intensive lifestyle intervention in Look-AHEAD: some T2DM patients benefit, other are harmed

Heterogeneity 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

Literature - De Vries TI, Dorresteijn JAN, Van der Graaf Y et al., - Diabetes Care 2019; dc190776.

Introduction and methods

Weight loss beneficially impacts metabolic control and CV risk factors in patients with type 2 diabetes (T2DM) [1,2]. Bariatric surgery may lower the risk of CV events in obese patients with T2DM [3]. It is, however, unknown whether weight loss through lifestyle intervention positively impacts CV outcomes in patients with T2DM.

The randomized Action for Health in Diabetes (Look AHEAD) trial evaluated an intensive lifestyle intervention program that promoted weight loss through decreased caloric intake and increased physical activity in overweight and obese patients with T2DM. The control group received regular diabetes support and education [4]. After a median follow-up of 9.6 years, the Look AHEAD trial was stopped prematurely due to a futility analysis. The intervention was found to lead to greater weight loss and greater reductions in HbA1c and CV risk factors, but CV event or mortality risk was not positively impacted by the intervention [1]. No subgroups based on a single baseline characteristic were identified that showed a significant treatment effect on CV outcomes. It is possible, however, that a combination of patient characteristics affects the effect of an intervention.

This post hoc analysis of the Look AHEAD trial therefore aimed to explore whether the intensive lifestyle intervention may be beneficial in reducing CV events in individual patients.

To explore the possible presence of heterogeneity of treatment effect (HTE), treatment effect (prediction of MACE) was first modeled with a Cox proportional hazards model based on the Look AHEAD population. The choice of predictors was based on a novel lifetime risk model in patients with T2DM [5]. To model treatment effect directly, treatment-by-covariate interaction terms for all predictors were added to the model. The predictive value of the model was assessed based on calibration plots of predicted vs. observed 10-year risks of MACE and the c-statistic was used as a measure for discrimination.

The new prediction model was then used to estimate 10-year risk of MACE for each study participant, both as if they had been randomized to the intervention, as well as to the control group. The treatment effect was defined as the 10-year risk with diabetes support and education minus the 10-year risk with the intensive lifestyle intervention.

Then, HTE for intensive lifestyle intervention was assessed by dividing the study population into quartiles based on predicted treatment effect. Characteristics associated with a high vs. low predicted benefit for the risk of MACE were identified.

Main results


This exploratory analysis of Look AHEAD trial data shows that the treatment effect of an intensive lifestyle intervention on the occurrence of MACE varies between patients, in a population of overweight and obese patients. The analysis suggests that there is a subgroup of patients in the Look AHEAD trial who benefitted from a lifestyle intervention aimed at weight loss, in terms of a lower risk of MACE. The analysis also suggests that part of the T2DM patients may experience harm from the intensive lifestyle intervention. This study identified several patient characteristics that are associated with a potential treatment benefit, among which no history of CVD, good control of type 2 diabetes, no use of insulin, higher socioeconomic status, and the absence of macroalbuminuria.


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