The Look AHEAD

(Action for Health in Diabetes) Trial

PUBHEPI 715June 2012

Jennifer Bauman, RN, BA, PCCN

“The Look AHEAD (Action for Health in Diabetes) Study is examining the long-term impact of an intensive lifestyle intervention, compared with

usual care, on cardiovascular morbidity and mortality in 5,145 overweight or obese

individuals with type 2 diabetes.”

(The Look AHEAD Research Group, 2011)

Obesity: It’s a BIG problem– Prevalence

• From 1987 to 2007, the fraction of adults who were overweight or obese increased from 44% to 63% of the U.S. adult population.

• Obese adults more than doubled during that same period, from 13% to 28%.

– Cost• Spending per capita for obese adults exceeded spending for adults of normal

weight by about 38% in 2007.• Spending in 2007 on obesity-related diseases averaged $2,030 for obese

adults and $1,090 for normal-weight adults, a difference of $940, which is approximately 60% of the difference in spending between normal weight and obese individuals.

• Increased prevalence of obesity is responsible for almost $40 billion of increased medical spending through 2006, including $7 billion in Medicare prescription drug costs.

• Estimated cost of obesity: $147 billion per year

Severe Obesity• The prevalence of overweight and mild obesity has

begun to stabilize, but the rates of severe obesity (BMI > 40 kg/m2) continue to rise – by approximately 52% in 5 years.

• Severely obese individuals have been excluded from the majority of clinical weight loss trials due to exclusion criteria and/or co-morbid conditions = lack of empirical evidence on weight loss strategies for this population

• Bariatric surgery is the recommended treatment approach, but it only reaches ~ 1% of the population and may not be the ideal treatment

(Unick, 2011)

Obesity: Definition and Risk Factors• Definition: BMI > 30 kg/m2

• Risk factors: inactivity, excessive calorie consumption and unhealthy dietary patterns, lack of sleep, certain medications (e.g. antidepressants, anti-seizure medications, diabetes medications, antipsychotic medications, steroids and beta blockers), medical conditions (e.g. Cushing’s syndrome, arthritis), genetics, family lifestyle, quitting smoking, pregnancy, age (i.e. menopause), social and economic factors (Mayo Clinic, 2012).

BMI Weight Status

Below 18.5 Underweight

18.5 - 24.9 Normal

25.0 - 29.9 Overweight

> 30.0 Obese

> 40.0 Extreme Obesity

Waist circumference: • At a higher risk for CVD and type 2

diabetes if abdomen > hips• Increased risk if >35 inches for women

or >40 inches for men

Obesity and CVD

• Known risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and pro-thrombotic state

• Predisposes or is associated with numerous cardiac complications such as CHD, heart failure, and sudden death through its impact on the cardiovascular system

(Poirier et al., 2005)

• Diabetes affects 25.8 million people of all ages = 8.3% of the U.S. population• About 1.9 million adults were newly diagnosed with diabetes in 2010 in the U.S.• An estimated 79 million American adults have pre-diabetes.• The leading cause of kidney failure, non-traumatic lower-limb amputations, and new cases

of blindness among adults in the United States.• Overall, the risk for death among people with diabetes is about twice that of people

without diabetes.• The 7th leading cause of death in the United States.• Adults with diabetes have heart disease death rates about 2 to 4 times higher than adults

without diabetes. • The risk for stroke is 2 to 4 times higher among people with diabetes.• Medical expenses for people with diabetes are more than 2 times higher than for people

without diabetes. • The total annual cost of diabetes is $174 billion. • Those with diabetes have about twice the risk of gum disease than those without diabetes.• People with diabetes are more susceptible to many other illnesses. • People with diabetes are twice as likely to have depression.

From http://diabetes.niddk.nih.gov/dm/pubs/statistics/#fast

Diabetes by the Numbers

Type 2 Diabetes

• The most prevalent type of diabetes – accounts for ~ 90% of patients with diabetes

• Usually occurs in people over 35 years of age (half of those diagnosed are > 55), 80-90% are overweight at time of diagnosis

• Greater in some ethnic populations: African Americans, Asian Americans, Hispanic Americans, Native Americans

(Lewis et al., 2007)

Type 2 Diabetes Pathophysiology• Most significant risk factor = OBESITY • Pancreas usually continues to produce endogenous

insulin but it is either insufficient for the needs of the body and/or is poorly utilized by the tissues (insulin resistance).

• Pancreas’ β cells “tire out” • Inappropriate and haphazard glucose production by

the liver • Production of hormones and cytokines by adipose

tissue = adipokines, especially adiponectin and leptin, which play a role in glucose and fat metabolism

(Lewis et al., 2007)

Type 2 Diabetes and CVD• Previous studies demonstrate that diabetic patients have

an increased rate of CVD-related morbidity, incidence in complications/poor outcomes, and risk of mortality – including MI, CVA, and PAD.

• Chronic hyperglycemia, dyslipidemia, and insulin resistance increase susceptibility to atherosclerosis

• Pro-thrombotic state• Alters function of multiple cell types, including

endothelium, smooth muscle cells, and platelets (Beckman, Creager, Libby, 2002)

• Type 2 diabetes is associated with two to fourfold increased risk for CVD (The Look AHEAD Research Group, 2003).

Obesity AND Type 2 Diabetes

Overweight or obese individuals with type 2 diabetes are at particularly high risk for CVD

morbidity and mortality

(The Look AHEAD Research Group, 2003)

Rationale for Clinical Trial• Short-term weight loss has been demonstrated to improve CVD risk

factors, no prospective randomized studies have examined the long-term consequences of intentional weight loss in overweight or obese populations.

• Several large randomized multicenter trials have demonstrated significant decreases in weight and increases in activity level for as long as 3 years with lifestyle interventions, most for only 1 year.

• Previous study by Goodpaster et al. was the first to examine effectiveness of an intensive lifestyle intervention on weight loss and CVD risk factors in the severely obese population, but this study excluded those with diabetes, and the sample size was small (Unick, 2011).

• Although previous studies have demonstrated reduction in risk of developing type 2 diabetes or hypertension with weight loss through lifestyle change, none have demonstrated that such interventions will reduce CVD morbidity or mortality

Objective and Specific Aims of Trial• Outcomes of interest: the long-term (up to 13.5

years) effects of ILI vs. control condition of diabetes support and education (DSE) on the combined incidence of serious cardiovascular events [cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke]

• Other research goals: comparisons of CVD risk factors, mortality, diabetes-related metabolic factors and complications, safety of the interventions, indices of general health, quality of life, and economic consequences

(The Look AHEAD Research Group, 2003)

Experimental Design• Participants randomized by center to ILI or DSE.• The participants’ own physicians provided all medical care

and made changes in medications, except for temporary changes in diabetes medications during periods of intensive weight loss in ILI

• Assessments completed annually, $100 honorarium provided– Measures (height, weight, blood pressure, blood work, medication

use, ABI) obtained by certified staff masked to the participants’ intervention assignment

– Maximal graded exercise test at baseline and submaximal exercise test at years 1 and 4

– Adherence to regimen assessed by attendence at treatment sessions and self-reported use of meal replacements from weekly diaries

(The Look AHEAD Research Group, 2011)

Intensive Lifestyle Intervention (ILI)

• Diet modification and physical activity (PA) to induce >7% weight loss at year one and to maintain this weight loss in subsequent years

• Assigned a calorie goal, using a portion-controlled diet (including liquid meal replacements) for increased dietary adherence

• At least 175 minutes of PA/week• Behavioral strategies, including self-monitoring, goal

setting, and problem-solving, were stressed

Intensive Lifestyle Intervention (ILI)

• Each session: weighed, self-monitoring records reviewed, and new lesson presented per standardized treatment protocol

• Seen weekly for first 6 months and 3x/month for next 6 months, with a combination of group and individual sessions

• During years 2-4, seen individually at least 1x/month, contacted another time each month via phone or e-mail, and offered a variety of approved group classes

(The Look AHEAD Research Group, 2011)

Diabetes Support and Education (DSE)

• Invited to 3 group sessions each year, which utilized a standardized protocol and focused on diet, PA, or social support

• Information on behavioral strategies was not presented

• Participants not weighed at these sessions(The Look AHEAD Research Group, 2011)

Target Population, Disease, and Recruitment

• Target population: overweight/obese patients with type 2 diabetes

• Recruitment: informational mailings, open screenings, advertisements, and referrals from health care professionals (2009)

Power and Sample Size

• A 15%–20% difference between ILI and DSE was identified as conveying significant public health benefit.

• 5000 participants followed up for a maximum of 11.5 years would yield 92% power (with two-sided α = 0.05) to detect an 18% relative difference in the composite primary endpoint (i.e., an absolute event rate of 3.125 per 100 person-years in the DSE group versus an absolute event rate of 2.562 per 100 person-years in the ILI group)

(Brancati et al., 2012).

Sample Size

• Assumptions: – (1) Rate of incident CVD in the DSE group would be 3.125% per year,

corresponding to the projected rate of incident CVD in a population of overweight and obese adults with type 2 diabetes eligible for participation in Look AHEAD

– (2) Cohort would be recruited uniformly over 2.5 years of follow-up– (3) 2% of participants would be lost to endpoint ascertainment

annually– (4) Participants lost to follow-up would be similar to their

counterparts in regard to both treatment and endpoint risk

(Brancati et al., 2012)

Inclusion Criteria

• Type 2 diabetes mellitus is determined by self-report with verification (medical records, current treatment, verification from personal health care provider, or fasting glucose 126 mg/dL, symptoms of hyperglycemia with casual plasma glucose 200 mg/dL or 2-hour plasma glucose 200 mg/dL after a 75-g oral glucose load on at least two occasions).

Inclusion Criteria• The number of subjects using insulin at the time of enrollment

will be monitored with a goal of 30% of the total. • After 3 months, those individuals who are ineligible because of

HbA1c, triglyceride, or blood pressure levels may be rescreened for eligibility.

• A history of uncomplicated myocardial infarction, coronary artery bypass surgery, percutaneous coronary angiography, atherectomy or stent placement, chronic stable angina pectoris, and stable New York Heart Association Class I or Class II congestive heart failure are permitted conditions for entry if the event or diagnosis of the condition occurred at least 3 months previously.

• Participants with a history of carotid or peripheral artery atherectomy, angioplasty, or vascular bypass surgery are also eligible if they meet functional criteria for inclusion

• Successful completion of two-week self-monitoring period and maximal graded exercise test prior to randomization

(Look AHEAD Research Group, 2003)

Exclusion Criteria

• Individuals >75 years of age (due to their increased risk of competing mortality and potential safety concerns related to weight loss)

• Individuals who have a clinical history strongly suggestive of type 1 diabetes are excluded.

Exclusion Criteria

Exclusion Criteria

Participant Selection

Baseline Characteristics• The 5145 participants recruited at 16 centers in the United States were

randomized between 2001 and 2004 , 2570 to ILI and 2575 to DSE • 63.3 % white, 15.6% African-American, 13.2% Hispanic, 5.1% American

Indian, and 1.0% Asian-American, which closely paralleled the ethnic distribution of diabetes in the NHANES 1999–2000 survey.

• Average age at entry was 59 ± 6.8 years (mean ± SD); 31.5% between 45-54 years of age, 51.5% were 55–64, and 17.0% ≥65 years of age

• 60% were women • 14.6% of participants were taking insulin at the time of randomization • 14.1 % had a history of cardiovascular disease – more men (21.2%)

than women (9.3%) had a history of cardiovascular disease • Few participants (4.4%) were current cigarette smokers compared to

16.2% in the NHANES 1999–2000 survey• 65% of participants had a first-degree relative with diabetes • Overall, BMI averaged 36 ± 5.9 kg/m2 at baseline with 83.6% of the

men and 86.0% of women having a BMI >30 kg/m2 and 17.9% of men and 25.4% of women having a BMI > 40 kg/m2

• 93% of the cohort is classified has having the metabolic syndrome using the criteria proposed by the National Cholesterol Education Program ATPIII panel

(The Look AHEAD Research Group, 2009)

Sample is younger, with more women, higher BMI, more educated, less likely to smoke suggesting that there was a self-selection bias among volunteers

Midcourse Correction

• Original power calculations were based on an expected CVD rate of 3.125% per year in the control group.

• A lower-than-expected rate of 0.7% in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations

• An Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues was created.

(Brancati, et al., 2012).

• 3 possible reasons for the unexpectedly low CVD event rates:– (1) Secular trends have resulted in lower

CVD incidence and CVD mortality in the United States

– (2) Study participants were even healthier than expected

– (3) The Graded Exercise Test (GXT) excluded participants most likely to develop CVD events

• Options considered by the EPWG:– (1) Watchful waiting– (2) Extend study duration– (3) Broaden definition of the primary endpoint

• The ideal additional endpoint(s) would fit the following 5 criteria: (a) related to obesity, (b) high clinical importance, (c) related to atherosclerotic CVD, (d) low risk of ascertainment bias, and (e) acceptable to stakeholders and audience

• Considered 9 endpoints: All-cause mortality (already a secondary endpoint), Hospitalized angina, Urgent revascularization, Hospitalized CHF, Incident chronic kidney disease (CKD), Incident obesity-related cancer, Incident left ventricular hypertrophy (LVH), Deep venous thrombosis/pulmonary embolism, Fractures

• Recommendations from the EPWG:• Expand the primary endpoint to include

hospitalized angina• Extend the duration of the study by 24 months

Brancati et al., 2012, p.116

Statistical Methods• Based on intent-to-treat principle• Alpha level of 0.05• At completion of study, will use survival analysis:

• Cochran-Mantel-Haenszel test for general association for frequency comparisons for discrete responses (unit weighing, stratified by clinical center)

• Cox proportional hazards model used to compare intervention arms in secondary analyses involving additional covariates (clinical center- and baseline-prevalent CVD).

Outcomes• The primary outcome of Look AHEAD is the time to incidence

of the first post-randomization occurrence of any of the following events over the planned follow-up period of up to 13.5 years: – Cardiovascular death (including fatal myocardial infarctions and

stroke)– Nonfatal myocardial infarction– Nonfatal stroke

• The secondary outcome consists of the time to the first occurrence of any of the following events: – Death (all causes)– Coronary artery bypass grafting and/or percutaneous coronary

angioplasty– Hospitalization for congestive heart failure– Carotid endarterectomy– Peripheral vascular procedures such as bypass or angioplasty(The Look AHEAD Research Group, 2003)

Results• When compared to those in DSE, participants in ILI

demonstrated:– Greater % weight losses (−6.15% vs −0.88%, p<.0001) – Greater improvements in the following:

• Fitness (12.74% vs. 1.96%, p < .0001), • HbA1c (A1c, −0.36% vs. 0.09%, p<.0001) – despite lower use of diabetes

drugs• Systolic blood pressure (SBP, −5.33 vs. −2.97 mmHg, p<.0001),• Diastolic blood pressure (DBP, −2.92 vs. −2.48 mmHg, p<.012)• HDL-cholesterol HDL-C, 3.67 vs. 1.97 mg/dl, p<.0001)• Triglycerides (−25.56 vs. −19.75 mg/dl, p<.0006)

– Reductions in LDL-C were greater in DSE than ILI (−11.27 vs. −12.84 mg/dl, p=.009), but adjusted for medication use, changes in LDL-C did not differ between the two groups.

– Although the greatest benefits were often seen at 1 year, ILI participants still had greater improvements than DSE in weight, fitness, HbA1c, SBP, and HDL-C at 4 years.

Results• Overall, most differences were greatest at year 1 and decreased by year 4• Fitness: participants in ILI maintained a mean weight loss of 4.7% compared

with 1.1% in DSE at 4 years (p<.0001) • HbA1C: greater improvements in HbA1c in ILI occurred despite lower use of

diabetes drugs. For those not using any diabetes drug (insulin or oral agents) at baseline, a larger proportion of DSE compared with ILI participants started on these medications each year.

• SBP: greater reductions in all four years• DBP and Triglycerides: initially greater reduction at year 1 and continued

through year 3, but no longer significant at year 4• HDL-C: increased gradually for both groups, 8–9% higher than baseline for ILI,

3–6% above baseline for DSE• LDL-C: both had significant reductions in years 1 and 2, although no difference

between the two. By years 3 and 4, DSE group had greater reduction due to increased lipid-lowering medications (i.e. statins). After adjusting for use of lipid-lowering medications at baseline and annually, the changes in LDL cholesterol were not significantly different between the ILI and DSE group at any of the 4 years or averaged across the 4 years.

• Initiation of medications: decreased in ILI, health benefits and cost-savings

Changes in Weight, HbA1c, Blood Pressure, HDL-C, Triglycerides, and LDL-C (unadjusted and adjusted for medication use).

Discussion and Interpretation

• Limitations:– Self-reporting – Volunteer bias, highly motivated individuals– Older age (45-75)– Severely obese individuals participated in group

sessions with less obese …. How would they respond if treated in groups with similar BMIs?

Criteria of Judgment• Consistency of the association: Results appear

comparable or better than those reported previously• Biological plausibility: YES• Correct temporal sequence: likely present, especially

due to extended length of trial• Specificity: likely present, although this population

has multiple co-morbidities which may decrease this• Dose-response relationship (between the magnitude

of weight loss and the observed change in cardiovascular risk factors): would be interesting for future analysis

Conclusions• Intensive lifestyle intervention can produce and maintain

significant weight losses and improvements in fitness in individuals with type 2 diabetes. Across four years of follow-up, those in ILI had better overall levels of glycemic control, blood pressure, HDL-C and triglycerides, and thus spent considerable time with lower CVD risk.

• In addition, the weight losses in Look AHEAD are impressive in light of the perception that individuals with diabetes have more difficulty losing weight than do their non-diabetic counterparts

• The magnitude of the effects for fitness, HDL-C, HbA1c and blood pressure have been associated with decreased cardiovascular events and mortality in prior medication trials and observational studies

• The critical question is whether these differences between groups in risk factors will translate into differences in the development of CVD-related events.

(The Look AHEAD Research Group, 2011)

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