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The Look AHEAD trial, evaluating the effects of weight loss on cardiovascular (CV) morbidity and mortality in overweight/obese people with type 2 diabetes (T2D), was interrupted after a median 9.5-year follow-up because the incidence of CV events was not different between the Intensive Lifestyle Intervention (ILI) and the control groups, and unlikely to statistically change thereafter. This made health providers and patients wondering about clinical value of diet and physical exercise in diabetic patients. Many factors may have made difficult to ascertain benefits of lifestyle intervention, besides the lower than predicted CV event rates. Among others, LDL-cholesterol was lowered more, with a higher use of statins, in the control group. Anyhow, ILI significantly improved numerous health conditions, including quality of life, CV risk factors and blood glucose control, with more diabetes remissions and less use of insulin.
The intervention aimed at weight loss by reducing fat calories, and using meal replacements and, eventually, orlistat, likely underemphasizing dietary composition. There is suggestive evidence, in fact, that qualitative changes in dietary composition aiming at higher consumption of foods rich in fiber and with a high vegetable/animal fat ratio favorably influence CV risk in T2D patients.
In conclusion, the Look AHEAD showed substantial health benefits of lifestyle modifications. Prevention of CV events may need higher attention to dietary composition, contributing to stricter control of CV risk factors. As a better health-related quality of life in people with diabetes is an important driver of our clinical decisions, efforts on early implementation of behavioral changes through a multifactorial approach are strongly justified.
Cardiovascular disease (CVD) is the main cause of death in the developed countries. Tobacco use, unhealthy diet, and sedentary habits are considered the main responsible of this high mortality [
]. According to this WHO analysis, up to 80% of premature heart disease, stroke, and diabetes could be prevented through improvement of these modifiable risk factors [
]. Accordingly, guidelines recommend lifestyle modifications towards the corrections of these unhealthy habits as the first-line approach for CVD prevention [
European Society of Cardiology (ESC); European Atherosclerosis Society (EAS) ESC/EAS guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
International Atherosclerosis Society An International Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia.
]. This is particularly true for individuals with type 2 diabetes mellitus who are at higher risk of CVD because of the common coexistence of other risk factors for CVD (e.g., hypertension and dyslipidemia) and its independently increased risk [
]. Moreover, randomized controlled trials have consistently shown that lifestyle interventions are able to reduce the incidence of diabetes in high risk populations [
In the last decades, the attention has therefore moved from increasing awareness of the relevance of lifestyle for health to the difficult task of implementing changes in unhealthy habits. On this pathway, debate has been arisen by the release of the primary results of the Look AHEAD (Action for Health in Diabetes) trial, presented at the 2013 Annual American Diabetes Association Meeting and at the same time published in the New England Journal of Medicine [
]. The Look AHEAD was the first trial evaluating the effects on cardiovascular morbidity and mortality of an intensive lifestyle intervention designed to achieve weight loss. This randomized controlled study, performed on 5145 overweight or obese men and women with type 2 diabetes in 16 centers in the USA, was interrupted after a median follow-up of 9.6 years instead of the planned 13.5 years, because the number of CV events did not differ between the Intensive Lifestyle Intervention (ILI) group and the Diabetes Support and Education (DSE) control group, and significant changes till the planned end of the study were very unlikely to occur.
This study translated a rather expected, intuitive finding into a scientifically based negative conclusion. The interruption of the trial for futility exposed health professionals and patients to scientific and lay media messages wondering on the value of diet and physical exercise in the prevention of what may be considered the most relevant diabetes complication, i.e. cardiovascular morbidity and mortality. Therefore, in order to avoid unjustified inferences, a strict evaluation of the results is warranted. Although it is not possible to exclude the possibility that weight loss has no effect on CVD in overweight/obese people with type 2 diabetes, we should take into consideration all factors that may have made difficult to ascertain the possible benefits of intensive lifestyle intervention, most of which are mentioned or discussed in the original paper [
The first relevant factor is that CVD event rates were much lower than expected, and therefore reduced the power of the study to demonstrate differences between the ILI and the DSE groups. A series of factors may have contributed (Fig. 1), starting from the downward secular trend for CVD in USA, likely consequent to the improved control of CVD risk factors and better care of acute and chronic CVD. A significant improvement in coronary heart disease risk over the past decade has been reported among U.S. adults with diabetes [
Trends in the risk for coronary heart disease among adults with diagnosed diabetes in the U.S.: findings from the National Health and Nutrition Examination Survey, 1999–2008.
Figure 1Factors likely contributing to the occurrence of low CVD event rates in the Look AHEAD trial. Abbr: T2D, type 2 diabetes mellitus; DSE, Diabetes Support and Education; ILI, Intensive Lifestyle Intervention; CVD, cardiovascular disease; RFs, risk factors.
on behalf of the Look AHEAD Study Group Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study.
]. The original power calculations were based on an expected CVD rate of 3.125% per year in the control group; in the first 2 years of follow-up it was instead 0.7%. As the power of the study could not be increased by a reasonable prolongation of the study, it was decided to modify the primary cardiovascular outcome, adding hospitalization for angina to the previously determined composite outcome of death for cardiovascular causes, nonfatal myocardial infarction and non-fatal stroke [
on behalf of the Look AHEAD Study Group Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study.
]. However, this clinically sound choice only increased the event rates to 1.83% in the ILI group and 1.92% in the DSE group. The main reason for the low rates during the trial was that the patients with type 2 diabetes participating in the trial were at relatively low CVD risk, for a number of reasons, some likely related to participants' selection criteria. Participants were highly motivated – they were required to pass a behavioral test which involved recording their food intake and physical activity for two consecutive weeks – and were able to complete a maximal exercise test to rule out risks of exercise during the study. Moreover, although a wide range of glycated hemoglobin levels (11% or less) was allowed for inclusion, the mean level at the start of the study was 7.3%, indicating a relatively good average glycemic control. This is in line with the fact that an established relationship with a primary care provider was required for inclusion in the study. In addition, an intensification of medical management of cardiovascular risk factors took place in both study groups during the trial. Indeed, LDL cholesterol levels were lowered more in the control group than in the intervention group, and this was associated with a higher use of statins in the control group. The mean difference in LDL cholesterol during 10 years of follow-up between the control and the intervention groups was 1.6 mg/dl (0.04 mmol/L). This difference cannot be considered as trivial since, based on results of primary and secondary prevention trials, a change of this entity would be predicted to correspond to almost 0.8% reduction in major CVD events [
International Atherosclerosis Society An International Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia.
]. Pleiotropic effects of statins could also play a role, and statins reduced hs-CRP levels in this trial with an additive effect to that of weight loss.
It should also be considered that changes in CVD incidence may develop over longer terms; we have just moved from the traditional calculation of CVD risk on a 10-year basis to a longer-term risk score based on a 30-year risk [
International Atherosclerosis Society An International Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia.
]. It is possible that if the trial had continued for a longer time, differences in CVD outcomes could have been observed. On the other hand, it is also true that on the long run it becomes difficult to maintain the separation between an intervention group and the comparison group. It is interesting that, although the interventions are discontinued, participants will continue to be monitored, which may provide more valuable information in the next years. The post-trial follow-ups of DCCT-EDIC and UKPDS studies, showing long lasting effects of clinical interventions on diabetes complications leave room for some hope.
A relevant information from this large, well done trial is that, despite the lack of effects on the occurrence of major CVD events, it confirmed that losing weight may substantially benefit overweight and obese people with type 2 diabetes as shown in the final and intermediate follow-up reports [
Look AHEAD Research Group Effectiveness of lifestyle interventions for individuals with severe obesity and type 2 diabetes: results from the Look AHEAD trial.
Look AHEAD Research Group Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial.
]. First of all, the ILI group showed a significant improvement in many CVD risk factors (Table 1), including systolic blood pressure – together with a lower use of antihypertensive medications-, and HDL cholesterol. Blood glucose control was also significantly improved: glycated hemoglobin was 0.22% lower in the ILI group than in the control group (mean between-group differences after baseline), and there was a higher rate of diabetes remission [
] and a reduction in the use of insulin in the ILI group. The higher rate of diabetes remission observed with the intensive intervention, although of small magnitude and mainly concerning patients with a short duration of the disease, is one more scientific evidence, in accordance with the results of DPS and DPP, that diabetes is the result of an unhealthy lifestyle, mainly related to nutritional habits and sedentarity. A series of other factors have been reported to be improved by the intensive intervention during the trial at the 1-y and 4-y follow-ups [
Look AHEAD Research Group Four-year change in cardiorespiratory fitness and influence on glycemic control in adults with type 2 diabetes in a randomized trial: the Look AHEAD Trial.
Look Action for Health in Diabetes Research Group Metabolic factors, adipose tissue, and plasminogen activator inhibitor-1 levels in type 2 diabetes: findings from the look AHEAD study.
Look AHEAD Research Group A 1-year lifestyle intervention for weight loss in individuals with type 2 diabetes reduces high C-reactive protein levels and identifies metabolic predictors of change: from the Look AHEAD (Action for Health in Diabetes) study.
Look AHEAD Research Group Intensive lifestyle intervention improves physical function among obese adults with knee pain: findings from the Look AHEAD trial.
Look AHEAD Research Group Effect of the look AHEAD study intervention on medication use and related cost to treat cardiovascular disease risk factors in individuals with type 2 diabetes.
Look AHEAD Research Group Prevalence and predictors of abnormal cardiovascular responses to exercise testing among individuals with type 2 diabetes: the Look AHEAD (Action for Health in Diabetes) study.
Sleep AHEAD Research Group of Look AHEAD Research Group A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes: the Sleep AHEAD study.
Look AHEAD Study Group Effect of a lifestyle intervention on change in cardiorespiratory fitness in adults with type 2 diabetes: results from the Look AHEAD Study.
Look AHEAD Research Group Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial.
In the Look AHEAD trial, the lifestyle intervention focused on achieving weight loss. At the 1-year follow-up, ILI participants had an average weight loss of 8.6% of their initial weight vs. 0.7% among the DSE group, changing respectively, to 6.2% vs. 0.9% at the 4-year follow-up, and 6.0% vs. 3.5% at the study end.
The nutrition intervention strategy focused on reducing calories from fat and on the use of meal replacements, also providing frozen meals. The weight loss medication orlistat was also an option to participants who lost <10% of initial weight. The emphasis given to weight loss may have induced undervaluation of the importance of the composition of the diet; conversely, more and more data are accumulating on the relevance of food choice in relation to the impact of diet on health outcomes. To this respect, it is likely that an intervention more focused on changes in dietary composition would have given different results in terms of CVD outcomes. In fact, there is very suggestive evidence that, in order to achieve the most powerful effect on cardiovascular risk in type 2 diabetic patients, weight reduction should be combined with increased physical exercise and changes in the diet composition aiming at a higher consumption of foods rich in fiber and with a high vegetable/animal fat ratio in addition to a reduction of salt intake. Recent data from the EPIC study showed that the intake of some food groups – fruit, vegetables, legumes, nuts, seeds, pasta and poultry – were associated with a lower, while soft drinks, butter, margarine and cakes with a higher mortality risk, and indicated that people with diabetes may benefit more from a healthy diet than people without diabetes [
Lifestyle factors and mortality risk in individuals with diabetes mellitus: are the associations different from those in individuals without diabetes?.
]. In an Italian middle-aged male population, a healthy Mediterranean dietary pattern showed a protective effect on the occurrence of fatal coronary heart disease events at 20 and 40 years [
]. In addition, evidence from intervention studies clearly indicates that changes in diet composition, independently from weight loss, are able to reduce CVD risk in individuals with or at risk for type 2 diabetes. In the primary prevention study PREDIMED, Mediterranean diets enriched in extra-virgin olive oil or in nuts reduced the primary outcome (acute myocardial infarction, stroke, or death from cardiovascular causes) compared with a low-fat American Heart Association diet [
]. A Cochrane intervention review was suggestive of a reduction in cardiovascular risk by modification of dietary fat, but not reduction of total fat, in long-term trials [
]. Dietary interventions aiming at improving the composition of the western diet favorably influence the main mechanisms that drive CVD risk in metabolic patients, i.e. insulin resistance, dyslipidemia, and hypertension. In isoenergetic conditions, decreasing saturated fatty acid and increasing monounsaturated fatty acid improves insulin sensitivity, although not in individuals with a high fat intake [
Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects.
]. A recent meta-analysis provided convincing evidence that low glycemic index diets, especially when accompanied by an increase in dietary fiber, reduce total and LDL-cholesterol, independently of weight loss [
]. In patients with type 2 diabetes, dietary fiber and low glycemic index foods improve LDL-cholesterol levels and postprandial triglyceride-rich lipoproteins – proposed as an independent CVD risk factor by several epidemiological studies [
Effects of a plant-based high-carbohydrate/high-fiber diet versus high-monounsaturated fat/low-carbohydrate diet on postprandial lipids in type 2 diabetic patients.
]. It is clinically relevant that qualitative dietary changes are easier to maintain on the long term compared with weight loss based interventions, whose effects, as confirmed in the Look AHEAD, decrease over time after the initial positive results.
The other component of the weight reduction program was 175 min per week of moderate-intensity physical activity and exercise. This target, although more ambitious than in the Diabetes Prevention Program (≥150 min/week) – because higher levels of physical activity are required to maintain weight loss [
American College of Sports MedicineAmerican College of Sports Medicine Position Stand Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults.
]. One more consideration relates to the fact that the activity program in the Look AHEAD relied on unsupervised at-home exercise, and therefore the adherence to the program was based on the participants' records. This may explain why some of the positive effects observed in the trial were related more to the changes in cardiorespiratory fitness than to the reported total time of physical activity. On the other hand, this could reflect the effect of more vigorous physical activity, which is a stronger determinant of cardiorespiratory fitness. Since it is more difficult to improve cardiorespiratory fitness in individuals with type 2 diabetes, it is possible that more exercise is required in these patients to induce changes in the occurrence of CVD [
In conclusion, while the effect of weight reduction on diabetes prevention is well demonstrated, that on CVD remains uncertain. Some factors in the Look AHEAD trial may have made the relative benefit of the intensive lifestyle intervention on CVD morbidity and mortality more difficult to demonstrate. However, the overall results of the trial do not indicate that diet and exercise are not important in the treatment of type 2 diabetes. On the contrary, they indicate that a modest weight loss can have substantial health benefits for overweight and obese people with type 2 diabetes, reinforcing the evidence that CVD risk factors can be corrected by lifestyle changes. For a long-term prevention of CVD events, other measures including a higher attention to the quality of diet and a stricter control of CV risk factors may also be needed. Waiting for further analysis from the trial's investigators and considering very unlikely, although desirable, a new trial on lifestyle intervention, we should value the existing evidence, including all the results of the lifestyle intervention on different health markers obtained in the Look AHEAD to give support to the implementation of multiple lifestyle changes in patients with type 2 diabetes. Indeed, the amelioration of the quality of life, as a result of many favorable changes in general health, is already a more than sufficient goal to guide our clinical decisions, confident of the impact of lifestyle interventions in patients with obesity and type 2 diabetes on quality of life, mood status and patients' views about exercise and nutrition [
]. Most likely, in order to reduce the risk of CVD in diabetic persons it is important that the lifestyle intervention is started early in the course of the metabolic derangements and is based on a multifactorial approach.
References
World Health Organization
Chronic diseases and health promotion. Preventing chronic diseases: a vital investment.
World Health Organization,
Geneva, Switzerland2005 (Available from:)
European Society of Cardiology (ESC); European Atherosclerosis Society (EAS)
ESC/EAS guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Trends in the risk for coronary heart disease among adults with diagnosed diabetes in the U.S.: findings from the National Health and Nutrition Examination Survey, 1999–2008.
Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial.
Four-year change in cardiorespiratory fitness and influence on glycemic control in adults with type 2 diabetes in a randomized trial: the Look AHEAD Trial.
A 1-year lifestyle intervention for weight loss in individuals with type 2 diabetes reduces high C-reactive protein levels and identifies metabolic predictors of change: from the Look AHEAD (Action for Health in Diabetes) study.
Effect of the look AHEAD study intervention on medication use and related cost to treat cardiovascular disease risk factors in individuals with type 2 diabetes.
Prevalence and predictors of abnormal cardiovascular responses to exercise testing among individuals with type 2 diabetes: the Look AHEAD (Action for Health in Diabetes) study.
Lifestyle factors and mortality risk in individuals with diabetes mellitus: are the associations different from those in individuals without diabetes?.
Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects.
Effects of a plant-based high-carbohydrate/high-fiber diet versus high-monounsaturated fat/low-carbohydrate diet on postprandial lipids in type 2 diabetic patients.
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