- Email: [email protected]
Looking again at the Look AHEAD study
Comment
Looking again at the Look AHEAD study Despite clear evidence that structured weight loss interventions reduce diabetes incidence in high-risk adults, it is unclear whether such benefits extend to prevention of cardiovascular disease (CVD) and other diabetes complications, and this controversy has influenced the scope of recommendations for lifestyle interventions.1 Although results from the Da Qing Diabetes Prevention Follow-up Study2 in China showed reduced CVD mortality, and findings from the Diabetes Prevention Program study3 showed reduced microvascular disease, these benefits were limited to women. Perhaps the biggest source of doubt about the role of weight loss on cardiovascular disease outcomes has come from the Look AHEAD study, which was the largest randomised controlled trial designed specifically to test the effect of lifestyle-based weight loss on CVD incidence in people with type 2 diabetes, and achieved perhaps the largest long-term cumulative weight loss ever for a major trial.4 Although the study showed benefits of the weight loss intervention on diverse outcomes, including chronic kidney disease, disability, depression, and sleep quality, there was no significant effect on CVD, which remains the single largest cause of morbidity and mortality in most adult populations.5–7 The main findings of Look AHEAD seemed to contradict the consistent observational epidemiological evidence associating adiposity with increased CVD, and physical activity and healthy diet with reduced CVD.8–10 However, randomised trials of lifestyle interventions have a higher standard to reach than do cohort studies in several ways. Whereas cohort studies compare people who have chosen or succeeded in a health-improving behaviour with those who have not, randomised trials have heterogeneous treatment effects at two stages: the effect of the intervention on behaviour and weight change, and the effect of behaviour and weight loss on health outcomes. The growing interest in personalised care has increased interest in understanding the heterogeneity of treatment responses.11 Unfortunately, previous attempts to find baseline characteristics that predict favourable response to lifestyle interventions have been inconsistent and generally unfruitful. The analysis by Aaron Baum and colleagues in The Lancet Diabetes & Endocrinology provides a novel
approach to assessing such heterogeneity as well as potential insight into the factors affecting the CVD outcome in Look AHEAD.12 The investigators used causal forest modelling to identify (in a random half of the trial data) and then validate (in the remaining half) the core factors explaining variation in the intervention effect in Look AHEAD. The analysis showed that two factors— baseline HbA1c and health status—distinguished people who would benefit from the weight loss intervention, and identified three relevant groups from these variables. First, the 24% of participants who had both low starting HbA1c (<6·8%) and good health status (>48 on SF-36) had an impressive 45% reduction in incidence of the composite primary outcome (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospital admission for angina). At the other extreme, the 16% who had low starting HbA1c but poor health status had twice the risk of the primary outcome, which was also statistically significant. Baum and colleagues’ results also suggests that, in hindsight, if this latter group had been excluded from the study, that there would have been a significant benefit of lifestyle intervention, albeit with a modest effect size and a large number needed to treat. The findings from Baum and colleagues’ analysis are difficult to interpret. The finding that people with low HbA1c and good health status benefited from the Look AHEAD intervention is consistent with other Look AHEAD findings, which showed that those with low HbA1c had a greater rate of partial remission from diabetes and lower health care utilisation than others.13 Speculatively, good baseline health status might prime participants for better adherence to the lifestyle intervention and a more favourable improvement in health, and lower baseline HbA1c might be a marker of less severe diabetes or better adherence to treatment regimens—the combination might therefore potentiate a better health outcome. However, the lack of any significant difference between these subgroups in compliance or metabolic risk factors in the supplemental analyses leaves this explanation unsatisfying. The finding of increased relative risk of the primary outcome among participants with low HbA1c and poor health status is intuitively puzzling and the very low absolute hazard ratio in the trial control group in this ostensibly
www.thelancet.com/diabetes-endocrinology Published online July 12, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30238-3
Lancet Diabetes Endocrinol 2017 Published Online July 12, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30238-3 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(17)30176-6
1
Comment
unhealthy subgroup raises the question of whether this observation is simply a chance finding. Despite the questions left unanswered by this analysis, novel and rigorous study of the heterogeneity in intervention response is important to guide personalised care, risk stratification, and translation of prevention studies to clinical and community settings. Variation in health behaviours remains an overwhelming determinant of chronic disease risk. As we enter an era characterised by increasing lifespans but persistent high prevalence of chronic disease and multimorbidity, more diverse menus of lifestyle interventions will be necessary to improve population health. Such developments will also place a greater demand on intervention effectiveness research to improve our understanding of who will benefit from what types of interventions, how to engage and retain those who will benefit, and how to extend the menu of effective approaches for those who do not benefit from current interventions.
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*Edward W Gregg, Rena Wing Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA (EWG); Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA (RW) [email protected] The authors declare no competing interests. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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Crandall JP, Knowler WC, Kahn SE, et al. The prevention of type 2 diabetes. Nat Clin Pract Endocrinol Metab 2008; 4: 382–93. Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014; 2: 474–80. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015; 3: 866–75. Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145–54. Look AHEAD Research Group. Impact of intensive lifestyle intervention on depression and health-related quality of life in type 2 diabetes: the Look AHEAD trial. Diabetes Care 2014; 37: 1544–53. Kuna ST, Reboussin DM, Borradaile KE, et al. Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes. Sleep 2013; 36: 641–9A. Look AHEAD Research Group. Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2014; 2: 801–09. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PloS One 2013; 8: e65174. Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation 2016; 133: 187–225. Fogelholm M. Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors. A systematic review. Obes Rev 2010; 11: 202–21. Basu S, Sussman JB, Hayward RA. Detecting heterogeneous treatment effects to guide personalized blood pressure treatment: a modeling study of randomized clinical trials. Ann Inter Med 2017; 166: 354–60. Baum A, Scarpa J, Bruzelius E, Tamler R, Basu S, Faghmous J. Targeting weight loss interventions to reduce cardiovascular complications of type 2 diabetes: a machine learning-based post-hoc analysis of heterogeneous treatment effects in the Look AHEAD trial. Lancet Diabetes Endocrinol 2017; published online July 12. http://dx.doi. org/10.1016/S2213-8587(17)30176-6. Gregg EW, Chen H, Wagenknecht LE, et al, for the Look AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA 2012; 308: 2489–96.
www.thelancet.com/diabetes-endocrinology Published online July 12, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30238-3
Looking again at the Look AHEAD study Despite clear evidence that structured weight loss interventions reduce diabetes incidence in high-risk adults, it is unclear whether such benefits extend to prevention of cardiovascular disease (CVD) and other diabetes complications, and this controversy has influenced the scope of recommendations for lifestyle interventions.1 Although results from the Da Qing Diabetes Prevention Follow-up Study2 in China showed reduced CVD mortality, and findings from the Diabetes Prevention Program study3 showed reduced microvascular disease, these benefits were limited to women. Perhaps the biggest source of doubt about the role of weight loss on cardiovascular disease outcomes has come from the Look AHEAD study, which was the largest randomised controlled trial designed specifically to test the effect of lifestyle-based weight loss on CVD incidence in people with type 2 diabetes, and achieved perhaps the largest long-term cumulative weight loss ever for a major trial.4 Although the study showed benefits of the weight loss intervention on diverse outcomes, including chronic kidney disease, disability, depression, and sleep quality, there was no significant effect on CVD, which remains the single largest cause of morbidity and mortality in most adult populations.5–7 The main findings of Look AHEAD seemed to contradict the consistent observational epidemiological evidence associating adiposity with increased CVD, and physical activity and healthy diet with reduced CVD.8–10 However, randomised trials of lifestyle interventions have a higher standard to reach than do cohort studies in several ways. Whereas cohort studies compare people who have chosen or succeeded in a health-improving behaviour with those who have not, randomised trials have heterogeneous treatment effects at two stages: the effect of the intervention on behaviour and weight change, and the effect of behaviour and weight loss on health outcomes. The growing interest in personalised care has increased interest in understanding the heterogeneity of treatment responses.11 Unfortunately, previous attempts to find baseline characteristics that predict favourable response to lifestyle interventions have been inconsistent and generally unfruitful. The analysis by Aaron Baum and colleagues in The Lancet Diabetes & Endocrinology provides a novel
approach to assessing such heterogeneity as well as potential insight into the factors affecting the CVD outcome in Look AHEAD.12 The investigators used causal forest modelling to identify (in a random half of the trial data) and then validate (in the remaining half) the core factors explaining variation in the intervention effect in Look AHEAD. The analysis showed that two factors— baseline HbA1c and health status—distinguished people who would benefit from the weight loss intervention, and identified three relevant groups from these variables. First, the 24% of participants who had both low starting HbA1c (<6·8%) and good health status (>48 on SF-36) had an impressive 45% reduction in incidence of the composite primary outcome (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospital admission for angina). At the other extreme, the 16% who had low starting HbA1c but poor health status had twice the risk of the primary outcome, which was also statistically significant. Baum and colleagues’ results also suggests that, in hindsight, if this latter group had been excluded from the study, that there would have been a significant benefit of lifestyle intervention, albeit with a modest effect size and a large number needed to treat. The findings from Baum and colleagues’ analysis are difficult to interpret. The finding that people with low HbA1c and good health status benefited from the Look AHEAD intervention is consistent with other Look AHEAD findings, which showed that those with low HbA1c had a greater rate of partial remission from diabetes and lower health care utilisation than others.13 Speculatively, good baseline health status might prime participants for better adherence to the lifestyle intervention and a more favourable improvement in health, and lower baseline HbA1c might be a marker of less severe diabetes or better adherence to treatment regimens—the combination might therefore potentiate a better health outcome. However, the lack of any significant difference between these subgroups in compliance or metabolic risk factors in the supplemental analyses leaves this explanation unsatisfying. The finding of increased relative risk of the primary outcome among participants with low HbA1c and poor health status is intuitively puzzling and the very low absolute hazard ratio in the trial control group in this ostensibly
www.thelancet.com/diabetes-endocrinology Published online July 12, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30238-3
Lancet Diabetes Endocrinol 2017 Published Online July 12, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30238-3 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(17)30176-6
1
Comment
unhealthy subgroup raises the question of whether this observation is simply a chance finding. Despite the questions left unanswered by this analysis, novel and rigorous study of the heterogeneity in intervention response is important to guide personalised care, risk stratification, and translation of prevention studies to clinical and community settings. Variation in health behaviours remains an overwhelming determinant of chronic disease risk. As we enter an era characterised by increasing lifespans but persistent high prevalence of chronic disease and multimorbidity, more diverse menus of lifestyle interventions will be necessary to improve population health. Such developments will also place a greater demand on intervention effectiveness research to improve our understanding of who will benefit from what types of interventions, how to engage and retain those who will benefit, and how to extend the menu of effective approaches for those who do not benefit from current interventions.
1 2
3
4 5 6 7
8 9 10 11
*Edward W Gregg, Rena Wing Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA (EWG); Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA (RW) [email protected] The authors declare no competing interests. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
2
12
13
Crandall JP, Knowler WC, Kahn SE, et al. The prevention of type 2 diabetes. Nat Clin Pract Endocrinol Metab 2008; 4: 382–93. Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014; 2: 474–80. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015; 3: 866–75. Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145–54. Look AHEAD Research Group. Impact of intensive lifestyle intervention on depression and health-related quality of life in type 2 diabetes: the Look AHEAD trial. Diabetes Care 2014; 37: 1544–53. Kuna ST, Reboussin DM, Borradaile KE, et al. Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes. Sleep 2013; 36: 641–9A. Look AHEAD Research Group. Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2014; 2: 801–09. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PloS One 2013; 8: e65174. Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation 2016; 133: 187–225. Fogelholm M. Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors. A systematic review. Obes Rev 2010; 11: 202–21. Basu S, Sussman JB, Hayward RA. Detecting heterogeneous treatment effects to guide personalized blood pressure treatment: a modeling study of randomized clinical trials. Ann Inter Med 2017; 166: 354–60. Baum A, Scarpa J, Bruzelius E, Tamler R, Basu S, Faghmous J. Targeting weight loss interventions to reduce cardiovascular complications of type 2 diabetes: a machine learning-based post-hoc analysis of heterogeneous treatment effects in the Look AHEAD trial. Lancet Diabetes Endocrinol 2017; published online July 12. http://dx.doi. org/10.1016/S2213-8587(17)30176-6. Gregg EW, Chen H, Wagenknecht LE, et al, for the Look AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA 2012; 308: 2489–96.
www.thelancet.com/diabetes-endocrinology Published online July 12, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30238-3