Look AHEAD

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Wing RR, et al. "Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes". The New England Journal of Medicine. 2013. 369(2):145-154.
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Clinical Question

Among overweight or obese patients with T2DM, does moderate weight loss and increased exercise reduce CVD and its complications?

Bottom Line

Moderate weight loss and increased exercise are not associated with reduction in CVD and its complications among overweight or obese patients with T2DM.

Major Points

T2DM confers increased risk for development of CVD. Despite the level A recommendation for weight loss in overweight or obese diabetics from the ADA,[1] the role of weight loss in long-term reduction of CVD risk in diabetics is unknown.

The 2013 Look Action for HEAlth in Diabetes (Look AHEAD) trial randomized 5,145 patients with T2DM and overweight or obesity to a support and education group or an intensive therapy group stressing weight-loss through caloric restriction and increased moderate intensity exercise. Throughout the 9.6 years of follow up, patients in the intensive therapy group lost more weight, exercised more, reached lower hemoglobin A1c levels, and required fewer medications (antihypertensives, statins, and insulin). Despite this, the intensive therapy group did not demonstrate any reduction in the composite primary endpoint of CV mortality, non-fatal MI, non-fatal stroke, or angina hospitalization. In fact, the trial was stopped early because of a positive futility analysis.

Differences between rates of cardioprotective medication use between the groups may account for some of the difference in outcomes[2] as statin use was lower in the intensive therapy group. The ADA recommends statin therapy for all diabetics with either CVD or age ≥40 years with ≥1 CVD risk factor (level A).[1] Furthermore, the degree of weight loss may have been inadequate[2] though the authors argue that the amount achieved by patients was realistic. In a separate publication, the same group showed a higher rate of remission of diabetes in the support and educational group at a four year interim analysis.[3]

In contrast to the negative results of Look AHEAD, PREDIMED (2013) demonstrated a reduction in development of CVD in at-risk patients (~50% with DM) with adoption of a Mediterranean diet when compared to a low-fat diet.

Guidelines

Published prior to the results of this trial.
ADA (2013)[1]

  • Weight loss for all overweight or obese patients with T2DM (level A)
  • Weight loss in the above population is likely effective at two years with a low-carbohydrate, low-fat calorie restricted, or Mediterranean diet (level A)

Design

  • Multicenter, randomized, open-label, comparative trial
  • N=5,145
    • Control (n=2,575)
    • Intensive therapy (n=2,570)
  • Setting: 16 US centers
  • Enrollment: 2001-2004
  • Median follow-up: 9.6 years (stopped early given futility analysis)
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, non-fatal MI, non-fatal stroke, or angina hospitalization

Population

Inclusion Criteria

  • Age 45-75 years old with a PMH of T2DM and overweight or obesity (BMI ≥25 kg/m2 or ≥27 kg/m2 if on insulin)
  • BP ≤160/100 mmHg
  • Hemoglobin A1c ≤11%
  • TG <600 mg/dL
  • Willingness to be randomized

Of note, patients with and without CVD were included in the trial.

Exclusion Criteria

  • T1DM
  • Adherence problems[4] (i.e. lack of informed consent, certain psychiatric disorders, relocation, weight loss >10 lbs in prior 3 months, bariatric surgery, etc.)
  • Diseases limiting lifespan or affecting safety[4] (i.e. pregnancy/nursing, non-melanoma skin cancer treatment in prior 5 years, HIV, active TB, MI or intervention in prior 3 months, UA, cardiac arrest, NYHA class III or IV HF, creatinine >1.4 mg/dL in women or >1.5 mg/dL in men, HBV/HCV etc.)

Baseline Characteristics

From the intensive therapy group.

  • Demographics: Age 58.6 years, female 59.4%
    • Race/ethnicity: Black 15.6%, Native American 5.1%, Asian/Pacific Islander 1.1%, White 63.1%, Hispanic 13.2%
  • Baseline health data: BMI 35.9 kg/m2, weight 101 kg, waist circumference 114 cm, hemoglobin A1c 7.2%, BP 128/70 mmHg, HDL cholesterol 43.4 mg/dL, LDL cholesterol 112 mg/dL, TG 115 mg/dL
  • PMH: CVD 14.2% (MI, stroke, HF, CABG, PCI, CEA, angioplasty, or aortic aneurysm repari), current smoker 4.6%
  • Baseline medications: Insulin 15.4%
  • DM duration: 5 years

Interventions

  • Randomization to a group:
    • Support and education - Diet, exercise, and social support groups occurring 3 times annually for the first 4 years then annually thereafter
    • Intensive therapy - Goal weight loss of ≥7% through caloric restriction (1200-1800 cal/day; <30% from fat and >15% from protein) and exercise (175 minutes of moderate-intensity exercise weekly) supported with group and individual counseling sessions occurring weekly in the first 6 months then with decreasing frequency
  • Both groups had medical therapy as directed by their treating physician

Outcomes

Presented as support and education vs. intensive therapy. 100 p-y represents event rate per 100 person-years.

Primary Outcome

CV mortality, non-fatal MI, non-fatal stroke, or angina hospitalization
1.92 vs. 1.83/100 p-y (HR 0.95; 95% CI 0.83-1.09; P=0.51)

Of note, angina was added to the primary outcome given a lower rate of the original primary endpoint in the first two years of the trial.

Secondary Outcomes

Individual outcomes
All-cause mortality: 0.86 vs. 0.73/100 p-y (HR 0.85; 95% CI 0.69-1.04; P=0.11)
CV mortality: 0.24 vs. 0.22/100 p-y (HR 0.88; 95% CI 0.61-1.29; P=0.52)
MI: 0.84 vs. 0.71/100 p-y (HR 0.84; 95% CI 0.68-1.04; P=0.11)
Fatal MI: 0.05 vs. <0.02/100 p-y (HR 0.44; 95% 0.15-1.26; P=0.13)
Non-fatal MI: 0.80 vs. 0.69/100 p-y (HR 0.86; 95% CI 0.69-1.06; P=0.16)
Angina hospitalization: 0.87 vs. 0.85/100 p-y (HR 0.97; 95% CI 0.80-1.19; P=0.79)
Stroke: 0.34 vs. 0.36/100 p-y (HR 1.05; 95% CI 0.77-1.42; P=0.78)
HF: 0.51 vs. 0.42/100 p-y (HR 0.80; 95% CI 0.61-1.04; P=0.10)
CABG: 1.21 vs. 1.14/100 p-y (HR 0.93; 95% CI 0.78-1.10; P=0.41)
CEA: 0.11 vs. 0.12/100 p-y (HR 1.10; 95% CI 0.64-1.87; P=0.74)
CV mortality, non-fatal MI, or non-fatal stroke
1.25 vs. 1.17/100 p-y (HR 0.93; 95% CI 0.79-1.10; P=0.42)

Note: this was the original primary outcome.

All-cause mortality, non-fatal MI, or non-fatal stroke
2.43 vs. 2.25/100 p-y (HR 0.93; 95% CI 0.82-1.05; P=0.23)
All-cause mortality, non-fatal MI, non-fatal stroke, angina hospitalization, CABG, PCI, HF hospitalization, CEA, or PVD
2.81 vs. 2.67/100 p-y (HR 0.94; 95% CI 0.84-1.05; P=0.29)

Additional Analyses

Weight annually
Lower in intensive group (Main effect -4; 95% CI -5 to -3; P<0.001)
Weight loss at end of the study
3.5% vs. 6.0% (no statistics given)
Physical fitness annually
Higher METs in intensive group (Main effect 0.6; 95% CI 0.5-0.8; P<0.001)
Waist circumference annually
Smaller in intensive group (Main effect -3.2; 95% CI -3.9 to -2.4; P<0.001)
Hemoglobin A1C
Lower in intensive group (Main effect -0.22; 95% CI -0.28 to -0.16; P<0.001)
Medication use[4]
Antihypertensive: Lower in intensive therapy group (OR 0.88; 95% CI 0.78-0.89; P=0.026)
Statin: Lower in intensive therapy group (OR 0.86; 95% CI 0.78-0.94; P<0.001)
Insulin: Lower in intensive therapy group (OR 0.74; 95% CI 0.66-0.82; P<0.001)
Blood pressure annually[4]
SBP Lower in intensive therapy group (Main effect -1.9; P<0.05)
DBP No difference (P=0.72)
Lipids annually
LDL cholesterol: Higher in intensive therapy group (Main effect 1.6; P<0.05)
HDL cholesterol: Higher in intensive therapy group (Main effect 1.2; P<0.05)
TG: No difference (P=0.261)

Subgroup Analysis

There is no significant difference in the prespecified subgroups including CVD, sex, race/ethnic group. There was, however, a non-significant trend in those with CVD at baseline as follows:

CVD
No: 1.42 vs. 1.23/100 p-y (HR 0.86; 95% CI 0.72-1.02)
Yes: 5.92 vs. 6.56/100 p-y (HR 1.13; 95% CI 0.90-1.42)
P-value for interaction: 0.06

Adverse Events

No difference between the treatment groups for severe hypoglycemia, gallstones, amputations, or HF.[4]

Fractures
Self-reported: 2.16 vs. 2.51/100 p-y (P=0.01)
Adjudicated: 1.64 vs. 166/100 p-y (P=0.83)

Criticisms

  • Underpowered
  • The weight loss in the intensive therapy group may have been insufficient[2]
  • A higher rate of statin use may have conferred a benefit to the support and education group[2]
  • The intensity of medical care between the two groups may have reduced complication rates
  • Unclear if other interventions would provide a larger benefit
  • Participants were likely more motivated than the average patient with T2DM

Funding

NIH and multiple other federal programs

Further Reading

  1. 1.0 1.1 1.2 American Diabetes Association "Executive summary: Standards of medical care in diabetes." Diabetes Care. 2013;36:S4-S10.
  2. 2.0 2.1 2.2 2.3 Gerstein HC. "Editorial: Do lifestyle changes reduce serious outcomes in diabetes?" The New England Journal of Medicine. 2013;369:189-190.
  3. Gregg EW et al. "Association of an intensive lifestyle intervention with remission of type 2 diabetes." JAMA. 2012;19(23):2489-2496.
  4. 4.0 4.1 4.2 4.3 4.4 Supplementary appendix