Looking AHEAD to Less Diet and Exercise for Patients with Diabetes?

Written By

Danielle C. Hebel, Pharm.D.
Erica F. Pearce, Pharm.D., BCPS

Reviewed By

David Dixon, Pharm.D., BCPS, CDE, CLS
Roshni Patel, Pharm.D.


The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013; 369: 145-54.

The recently published Look AHEAD trial found intensive lifestyle interventions had no benefit on cardiovascular (CV) morbidity and mortality in patients with diabetes mellitus (DM).  Could the results possibly be valid?  Should we stop emphasizing diet and exercise? In patients with DM, CV disease is the leading cause of morbidity and mortality.  Preventing CV disease has been traditionally accomplished by addressing modifiable risk factors and encouraging weight loss through lifestyle interventions. The American Diabetes Association (ADA) recommends weight loss through diet and at least 150 minutes of moderate-intensity aerobic physical activity per week, as well as resistance training at least twice per week.1 These guidelines are the cornerstone of the recommendations made by clinicians.  However, few studies have evaluated the effect of weight loss on CV mortality in patients with DM.  One meta-analysis showed that intentional weight loss had a small benefit on all-cause mortality in patients with obesity-related risk factors, such as type 2 DM.2  A review of epidemiological studies on weight loss and mortality in type 2 DM concluded that there was no relationship between weight loss and mortality.3 None of the studies were designed to test the hypothesis that weight loss improves CV outcomes or control potential confounders, such as unintentional weight loss or baseline body-mass index (BMI).2,3 Therefore, it has been unknown whether intensive lifestyle interventions decrease CV morbidity and mortality in overweight or obese patients with DM – until now.

The Action for Health in Diabetes (Look AHEAD) investigators conducted a randomized, controlled trial to determine the long-term CV impact of an intensive lifestyle intervention in overweight/obese patients with type 2 DM.4  The trial enrolled 5,145 patients at 16 centers across the United States between ages 45-75 years with a BMI of ≥ 25 kg/m2, A1c ≤ 11%, blood pressure < 160/100 mm Hg, triglycerides < 600 mg/dL, and the ability to complete an exercise test.  Patients were randomly assigned to one of two interventions:

  • Intensive lifestyle intervention (ILI):  Lifestyle counselors actively worked with patients to help them reach the 7% weight loss goal through reduced caloric intake (1200 - 1800 kcal/day) and increased physical activity (175 minutes/week).
  • Phase I (Year 1): three group education sessions per month and one individual counseling session per month for 26 weeks; then at least one of each session per month for months 7-12.
  • Phase II (Year 2-4): one individual counseling session per month and one contact per month via telephone, postcard, or email; plus optional attendance at group meetings.
  • Phase III (Year 4 and beyond): two individual meetings per year; optional contact via newsletter, phone, or other means.
  • Diabetes support and education (DSE): The control group received optional group education sessions three times yearly for four years, then annually thereafter.

The primary outcome of the trial was a composite of death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for angina. The risk reduction expected for the primary outcome was 18% between the two groups.  Three secondary composite outcomes included: death from CV causes, nonfatal MI, or nonfatal stroke; death from any cause, MI, stroke, or hospitalization for angina; and death from any cause, MI, stroke, hospitalization for angina, carotid endarterectomy, coronary artery bypass graft, percutaneous coronary intervention, heart failure, or peripheral vascular disease.

The trial was stopped early after a mean follow-up of 9.6 years because no significant differences were found between the two groups for the primary (HR 0.95, 95% CI [0.83-1.09], p = 0.51) or secondary outcomes in spite of significant weight loss and reductions in other CV risk factors favoring the ILI group.

Table 1
Outcome ILI
(end of study)
(end of study)
(end of study)
Mean % Weight Loss   6.0%   3.5% p < 0.001
Mean SBP (mmHg) 128 126 129 127 p < 0.05
Mean DBP (mmHg) 70 66 70 66 p = 0.72
Mean A1c (%) 7.26 7.33 7.32 7.44 p < 0.001
Mean LDL (mg/dL) 112 90 112 88 p < 0.05
Mean HDL (mg/dL) 43.5 48.7 43.5 47.8 p < 0.05

SBP = systolic blood pressure, DBP = diastolic blood pressure, LDL = low-density lipoprotein, HDL = high-density lipoprotein

The trial utilized a composite outcome and had to add additional criteria to the primary outcome during the study and extend the follow-up time by two years due to low event-rates. It seems the expected risk reduction was unrealistic and therefore the study may have been underpowered.  There is also a potential healthy user bias as patients who enrolled in this study were not like the typical poorly controlled patients with multiple CV risk factors that we often see in practice.  Moreover, the DM education and medical management received by the control group was more than what many patients receive in clinical practice.  Further, ILI group patients were less likely to be taking CV risk-lowering medications during the trial than the patients in the control group (antihypertensive OR 0.88, 95% CI [0.78 - 0.89], p=0.026; statins OR 0.8, 95% CI [0.78 to 0.94], p=0.001) which potentially narrowed the differences between the two groups.  Lastly, ILI group patients regained some of the weight they initially lost at the beginning of the trial.  Perhaps maintenance of weight loss or greater weight loss (e.g. > 10%) is necessary to truly impact CV morbidity and mortality.

While the results of the Look AHEAD trial are disappointing, the study limitations likely explain why.  Are there other reasons to recommend diet and exercise? Patients in the ILI group experienced significant improvements in A1c, HDL cholesterol, and blood pressure despite a decreased use of insulin and other medication.  This supports the current ADA recommendations for weight loss to improve glycemic control and CV risk factors.  In addition, the intensive lifestyle intervention lowered the risk of developing urinary incontinence5, sleep apnea6, and depression7 and led to improvements in quality of life8 and physical functioning.9  These very important patient-centered benefits should not be overlooked.

There are many positive health outcomes derived from intensive lifestyle changes, including improvements in blood glucose, lipids, and blood pressure.  Intensive lifestyle interventions may not lower CV risk in patients who already have well-controlled glucose, lipids, and blood pressure, but does ILI lower CV risk in patients who are poorly controlled?  Should these results prompt us to put more effort toward assuring that all patients are receiving guideline-recommended drug therapies to mitigate CV risk? Or should we continue to Look AHEAD and recommend intensive lifestyle interventions to all patients with DM?



When I first heard about this on the news, my first thought was 'how did the patients feel?'. As you mention, improvements in quality of life and physical functioning can certainly not be overlooked. Great summary.