Editor's Note: Commentary on The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-154.

Background

Whenever a large multicenter, investigator-initiated, NIH-funded clinical trial is stopped early for futility, it is inevitable that there will be post-hoc evaluations. Look AHEAD was the largest and longest randomized clinical trial designed to show that improved lifestyle can prevent cardiovascular disease in patients with diabetes.²

Methods

Sixteen study centers in the U.S. randomly assigned patients to either intensive lifestyle intervention (ILI) or a Diabetes Support and Education (DSE) comparison group. Specific ILI goals were a sustained weight loss of ≥ 7% of initial weight and increased physical activity to ≥ 175 minutes a week. The DSE comparison group was provided detailed verbal and written diabetes education at baseline, and periodic health lectures, designed to maintain their participation without being in the highly desired ILI group. Many novel design features were adopted.³

1. Personal Physician: Look AHEAD required that both ILI and DSE participants have an established relationship with a primary care provider, a design to reduce cost and mirror real clinical practice. Because life style cannot be blinded, Look AHEAD chemistries were reported annually to each participant's physician who shared essential results with the patient. Participants and their health care providers received annual reports on their updated cardiovascular risk factors and the goals recommended by the American Diabetes Association. All medication adjustments were made by each participant's health care provider.
2. Weight Loss: Because many obese adults cannot sustain weight loss by lifestyle alone for more than one year, the ILI group used an extensive tool box of other interventions to hasten and sustain weight loss, including liquid diets, low-calorie snacks, pre-packaged portion-control meals, paid memberships in commercial weight control and exercise clubs, and weight-loss medication if needed.
3. Physical activity criteria were modest. ILI participants were asked to walk at brisk pace for at least 50 minutes a week, counting activity bouts of ≥ 10 minutes toward a weekly goal, and did most of their physical activity at home where unsupervised physical exercise is easier to implement and sustain.
4. Eligibility: Participants were required to have a BMI ≥25.0 (unless using insulin) and a glycated hemoglobin level of 11% or less; a systolic blood pressure < 160 mm Hg and a diastolic blood pressure < 100 mm Hg; and triglycerides < 600 mg/dl, and no manifest cardiovascular disease. In addition they had to successfully complete a maximal graded exercise tolerance test (GXT), "showing it would be safe to exercise". The GXT protocol was designed so that most participants could safely achieve maximum voluntary exertion over eight to 12 minutes.
5. These eligibility criteria yielded unusually healthy overweight or obese patients with diabetes. At baseline 22% of potential participants without known heart disease were ineligible because they had an abnormal GXT, of whom 12% had impaired exercise capacity, 7.6% had ST segment depression, 5.5% had abnormal heart rate recovery, 1.1% had exercise-induced angina, and 0.7% had ventricular arrhythmia.

Results

Randomization was successful, with similar baseline characteristics for ILI and DSE groups, and with high participation rates in both groups initially. By one year, ILI participants showed greater improvement than DSE participants in weight loss (8.6%), fitness, glycated hemoglobin levels, and in all measured cardiovascular risk factors, except LDL cholesterol. Much smaller but still significant differences were observed at trial end 10 years later—see Figure 1.¹

It was obvious within two years that incident heart disease rates were lower than expected. Investigators later included 711 Look AHEAD subjects with a self-reported history of heart attack or stroke (14.6 % of the ILI group and 13.8 % of the DSE group);⁴ outcomes were expanded to include other cardiovascular events including heart failure, coronary artery revascularization, peripheral arterial disease, and hospitalization for angina pectoris. The trial duration was increased from 10 to 15 years.

Conclusions

These changes were too little too late. In 2012, Look AHEAD was closed after 10 years by the DSMB, when only 821 patients had a primary cardiovascular event (418 in DSE, 403 in ILI, hazard ratio 0.95 [0.83 – 1.09]).

Commentary

Personal physicians were a clever idea because they provided medical management and medication for overweight patients with diabetes, including the DSE participants, who could not be medically ignored for 10 years. Medications to prevent heart disease were prescribed to both groups by their personal health care providers, which likely reduced the number of CVD events and obscured ILI and DSE differences, as shown in the Table.¹

Table. Use (Proportion) of Specific Medications by Treatment Group.
	Baseline		End of Study
Medications	DSE Mean (95% CI)	ILI Mean (95% CI)	DSE Mean (95% CI)	ILI Mean (95% CI)
Hypertension Medications	0.72 (0.7, 0.74)	0.73 (0.71, 0.74)	0.88 (0.86, 0.89)	0.87 (0.85, 0.88)
Statins	0.44 (0.42, 0.46)	0.44 (0.42, 0.46)	0.74 (0.71, 0.76)	0.71 (0.69, 0.73)
Insulin	0.16 (0.15, 0.18)	0.15 (0.14, 0.16)	0.41 (0.38, 0.43)	0.36 (0.33, 0.38)
Angiotensin Converting Enzymes	0.45 (0.43, 0.46)	0.43 (0.41, 0.45)	0.5 (0.47, 0.52)	0.5 (0.47, 0.52)
Angiotensin Receptor Blockers	0.15 (0.14, 0.17)	0.16 (0.15, 0.17)	0.32 (0.29, 0.34)	0.31 (0.28, 0.33)
Beta Blockers	0.2 (0.19, 0.22)	0.22 (0.21, 0.24)	0.38 (0.36, 0.4)	0.35 (0.33, 0.37)
Calcium Chanel Blockers	0.2 (0.19, 0.22)	0.18 (0.17, 0.2)	0.26 (0.24, 0.28)	0.23 (0.21, 0.25)
Biguanides	0.61 (0.59, 0.63)	0.62 (0.6, 0.64)	0.67 (0.65, 0.67)	0.67 (0.64, 0.69)
DSE = diabetes support and education, ILI = intensive lifestyle intervention

Maximum GXT and no known heart disease criteria selected unusually healthy patients with diabetes and almost certainly reduced the incidence of cardiovascular events during Look AHEAD. A normal GXT in a patient without known heart disease is not necessary for the proposed level of physical activity. Few primary care physicians obtain a GXT before prescribing brisk walking to patients without known CVD, whether or not they have diabetes.

ILI focused on achieving weight loss through caloric restriction and increased physical activity. Perhaps an intervention using a different diet, for example, the Mediterranean diet, might have had a different outcome.¹

The design and protocol were based on many novel choices adopted to reduce costs and risks and promote retention. Overall these choices could explain reduced CVD rates and the futility of Look AHEAD. Alternatively, it is possible that macrovascular disease cannot be prevented or slowed by weight loss within 10 years in adults, particularly those who already have had diabetes for an average of 14 years.

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References

1. Look AHEAD Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-154.
2. Wadden TA, West DS, Delahanty L, et al. The Look AHEAD study: a description of the lifestyle intervention and the evidence supporting it. Obesity (Silver Spring) 2006;14:737-752.
3. Ryan DH, Espeland MA, Foster GD, et al. Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials 2003;24:610-628.
4. Gregg EW, Chen H, Wagenknecht LE, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA 2012;308:2489-2496.

Keywords: Cardiovascular Diseases, Diabetes Mellitus

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