Week 45 – Look AHEAD

“Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes”

by the Look AHEAD (Action for Health in Diabetes) Research Group

N Engl J Med. 2013 Jul 11;369(2):145-54. [free full text]

NIH treatment guidelines recommend weight loss in patients with T2DM and overweight or obesity. Such weight loss is associated with improvements in glycemic control, hypertension, and quality of life. While retrospective cohort studies and a prospective trial of bariatric surgery in T2DM suggested that weight loss was associated with reduction in rates of cardiovascular events and mortality, no prospective trial has demonstrated such benefits from non-surgical weight loss. The Look AHEAD study was designed to determine if aggressive lifestyle intervention for weight loss in T2DM could provide benefits in hard cardiovascular outcomes.

Population: patients with T2DM, age 45-75, and BMI 25+ (27+ if on insulin), A1c < 11%, SBP < 160 mmHg, DBP < 100 mmHg, and the ability to complete a maximal exercise test

Intervention: an “intensive lifestyle intervention” with goal weight loss ≥ 7.0%, implemented via weekly group and individual counseling (decreasing in frequency over course of study). Specific recommended interventions: caloric restriction to 1200-1800 kcal/day, use of meal-replacement products, ≥ 175 min/wk of moderate-intensity exercise

Comparison: “diabetes support and education” comprised of three group meetings per year focused on diet, exercise, and social support (yearly meetings starting year 5)
Outcome:
Primary – composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for angina.

Of note, hospitalization for angina was not a pre-specified component of the primary outcome. It was added 2 years into the trial after event rates of the other cardiovascular components were lower than expected.

Secondary

  • composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke (the original primary outcome)
  • composite of death (all-cause), nonfatal MI, nonfatal stroke, hospitalization for angina
  • composite of death (all-cause), nonfatal MI, stroke, hospitalization for angina, CABG, PCI, hospitalization for heart failure, or peripheral vascular disease

Results:
2570 patients were randomized to the intensive lifestyle intervention (ILI) group, and 2575 were randomized to the diabetes support and education (DSE) group. Baseline characteristics were similar in both groups. Mean BMI was 36.0, and 14% of patients had a history of cardiovascular disease.

At one year, mean weight loss from baseline was 8.6% in the ILI group and 0.7% in the DSE group (p < 0.001); however, weight loss at the end of the study was 6.0% in the ILI group and 3.5% in the DSE group (p < 0.001). The average group difference in A1c was 0.22% lower in the ILI group (p < 0.001) although A1c values were slightly higher than baseline in both groups at the end of the study (see Figure 1D for the time course).

The trial was terminated prematurely after interim analysis revealed that the likelihood of a significant positive primary result was approximately 1%. Median follow up was 9.6 years at the time of termination.

There was no group difference in rates of the primary composite cardiovascular endpoint. The endpoint occurred in 403 patients in the ILI group and 418 patients in the DSE group (1.83 and 1.92 events per 100 person-years, respectively; HR 0.95, 95% CI 0.83-1.09, p = 0.51).

There were no group differences in rates of the secondary composite outcomes.

Implication/Discussion:
Among patients with T2DM and overweight or obesity, an intensive lifestyle intervention for weight loss was not associated with improved cardiovascular outcomes, when compared to a control group-based diabetes support and education intervention.

Overall, this trial was a notable failure. Despite the trial’s adequate power and its authors shifting the goalposts at 2 years into the study, the intervention did not demonstrate “hard” cardiovascular benefits. Furthermore, generalizability of this study is limited by its exclusion of patients who could not complete a maximal-fitness test at baseline. With respect to diet, this trial did not address diet composition, only caloric restriction and increased physical activity.

The authors suggest that “a sustained weight loss of more than that achieved in the intervention group may be required to reduce the risk of cardiovascular disease,” and thus the trial failed to return a positive result.

Weight loss in patients with T2DM and overweight or obesity remains a Class A recommendation by the American Diabetes Association. The ADA also notes that weight loss may be achieved at 2 years with a “Mediterranean” diet. The 2013 PREDIMED study demonstrated that such a diet reduces the risk of ASCVD in high-risk patients.

Further Reading/References:
1. Look AHEAD @ Wiki Journal Club
2. American Diabetes Association. “Executive Summary: Standards of Medical Care in Diabetes – 2013.”
3. PREDIMED @ Wiki Journal Club

Summary by Duncan F. Moore, MD

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