Action for Health in Diabetes - Look AHEAD

Oct 04, 2016
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Author/Summarized by Author:
Anthony A. Bavry, MD,MPH,FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
National Institutes of Health
Date Published:
08/30/2016
Date Updated:
10/04/2016
Original Posted Date:
06/24/2013
References

Contribution To Literature:

The Look AHEAD trial failed to show that intensive lifestyle intervention reduced the incidence of adverse cardiovascular events.

Description:

The goal of the trial was to evaluate a strategy of intentional weight loss among overweight or obese patients with type 2 diabetes.

Study Design

  • Randomized
  • Parallel
  • Stratified

Patient Populations:

  • Patients 45-75 years of age with type 2 diabetes, body mass index ≥25 kg/m2, glycated hemoglobin ≤11%, systolic blood pressure <160 mm Hg, diastolic blood pressure <100 mm Hg, triglyceride level <600 mg/dl, and ability to complete a maximal exercise test

    Number of screened applicants: 28,622
    Number of enrollees: 5,145
    Duration of follow-up: median follow-up 9.6 years
    Mean patient age: 59 years
    Percentage female: 59%

Primary Endpoints:

  • Cardiovascular death, myocardial infarction, stroke, or hospitalization for angina

Drug/Procedures Used:

Overweight/obese patients with type 2 diabetes were randomized to an intensive lifestyle intervention that promoted decreased caloric intake and increased physical activity (n = 2,570) versus usual care with diabetes support and education (n = 2,575).

Intensive lifestyle intervention consisted of sessions with a nutritionist and personal trainer, as well as group sessions for support and reinforcement. Target weight loss in the intensive lifestyle intervention group was at least 7% of initial body weight.

The usual care groups received diabetes support and education.

Principal Findings:

Overall, 5,145 patients were randomized. The mean age was 59 years, 59% were women, 14% had a history of cardiovascular disease, and mean body mass index was 36 kg/m2. The mean glycated hemoglobin was 7.2%, mean systolic blood pressure was 128 mm Hg, mean high-density lipoprotein cholesterol was 43 mg/dl, and mean low-density lipoprotein cholesterol was 112 mg/dl.

Average weight loss from baseline to 1 year was -8.6% in the intensive lifestyle intervention group versus -0.7% in the control group (p < 0.001).

- Change in mean fitness: 20.9% versus 5.8% (p < 0.001)
- Change in glycated hemoglobin: -0.64% versus -0.14% (p < 0.001)
- Change in systolic blood pressure: -6.8% versus -2.8% (p < 0.001)
- Change in low-density lipoprotein cholesterol: -5.2% versus -5.7% (p = 0.49)
- Change in high-density lipoprotein cholesterol: 3.4% versus 1.4% (p < 0.001)
- Change in the proportion of patients at goal glycated hemoglobin (<7%), blood pressure (<130/80 mm Hg), and low-density lipoprotein cholesterol (<100 mg/dl): 12.8% versus 6.5% (p < 0.001), respectively for intensive lifestyle intervention versus control

Average weight loss from baseline to 4 years was -6.2% in the intensive lifestyle intervention group versus -0.9% in the control group (p < 0.001).

- Change in mean fitness: 12.7% versus 2.0% (p < 0.001)
- Change in glycated hemoglobin: -0.36% versus -0.09% (p < 0.001)
- Change in systolic blood pressure: -5.3% versus -3.0% (p < 0.001)
- Change in low-density lipoprotein cholesterol: -11.3% versus -12.8% (p = 0.009)
- Change in high-density lipoprotein cholesterol: 3.7% versus 2.0% (p < 0.001), respectively for intensive lifestyle intervention versus control

The trial was terminated early at a median of 9.6 years of follow-up due to futility in showing a difference in adverse cardiovascular events. Mean follow-up was planned to 13.5 years.

The primary outcome, incidence of cardiovascular death, myocardial infarction, stroke, or hospitalization for angina, occurred at a rate of 1.8 events/100 person-years in the intervention group versus 1.9 events/100 person-years in the control group (p = 0.51).

- Cardiovascular death: 0.22 vs. 0.24, respectively for intervention vs. control
- Myocardial infarction: 0.69 vs. 0.80, respectively
- Stroke: 0.36 vs. 0.34, respectively
- Hospitalization for angina: 0.85 vs. 0.87, respectively

The primary outcome (adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.65–0.99; p = 0.039) and secondary outcome (adjusted HR 0.79, 95% CI 0.66–0.95; p = 0.011) were lower among those in the intensive lifestyle group who lost at least 10% of their bodyweight compared with the control group.

Interpretation:

 Among overweight/obese patients with type 2 diabetes, intensive lifestyle intervention failed to reduce the incidence of adverse cardiovascular events. As a result, the trial was terminated early due to futility. Despite no benefit on the primary outcome, intensive lifestyle intervention resulted in significant weight loss and reduced the prevalence of cardiovascular risk factors; however, this benefit became somewhat attenuated between 1 and 4 years. The control group had modest improvements in cardiovascular risk factors and even had a lower low-density lipoprotein cholesterol level versus the intensive lifestyle intervention group, which might have contributed to the overall null trial findings.

The cardiovascular event rate during the study was lower than anticipated. This likely reflects good background therapy (e.g., antiplatelet agents, statins) among study participants. Also, diabetes is but one component of a patient’s overall risk for an adverse cardiovascular event.

References:

The Look AHEAD Research Group. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2016;Aug 30:[Epub ahead of print].

The Look AHEAD Research Group. Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes. N Engl J Med 2013;Jun 24:[Epub ahead of print].

National Institutes of Health News Release. Weight loss does not lower heart disease risk from type 2 diabetes. Available at: http://www.nih.gov/news/health/oct2012/niddk-19.htm. Accessed 10/19/2012.

Look AHEAD Research Group, Wing RR. 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. Arch Intern Med 2010;170:1566-75.

The 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. Diabetes Care 2007;30:1374-83.

Keywords: Myocardial Infarction, Stroke, Life Style, Follow-Up Studies, Platelet Aggregation Inhibitors, Weight Loss, Diabetes Mellitus, Type 2, Lipoproteins, Blood Pressure, Risk Factors, Glycated Hemoglobin A, Cholesterol, Body Mass Index, Cardiovascular Diseases, Motor Activity, Obesity, Medical Futility, Energy Intake, Nutritionists, Triglycerides, Exercise Test


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