Posts Tagged ‘Look Ahead’

Look AHEAD provides insights on the role of genes in weight loss

September 3rd, 2015

While the Look AHEAD Clinical Trial was discontinued some time ago, and while some the interpretations of the study remain controversial, continuing studies are showing some interesting interactions between behavior and genes. Jeanne Mc Caffery and colleagues have published one study showing that variations in the FTO and BDNF genes predicted weight regain across treatment arms.  Another study from a number of over-lapping researchers shows that variations in genes can affect the frequency of eating episodes and their composition as well. Click here for Dr. Arya Sharma’s recent post on a landmark study establishing how the FTO gene works.

 

Statin Use on the Rise

January 6th, 2015

CDC reports statin usage for the control of cholesterol has increased  by one-third over the past decade. In 2012, 28% of people over age 40 reported using a cholesterol-lowering medication, up from 2003 rate of 20%. Most of the increase was in statins. 71% of adults with cardiovascular disease and 54% of adults with high cholesterol reported medication usage to control their cholesterol, according to an article in the Washington Post by Tanya Lewis.

The high use of statins has several implications for persons with obesity. Obviously, this trend improves the health of many persons with obesity and  are at greater risk of cardiovascular disease. However, it can also be a confounding factor in research studies. Looking for changes in cardiovascular disease through weight loss (by any method) can be more difficult to find because of the effectiveness of statins. High use of statins was referenced as one of the reasons by the Look Ahead trial was terminated early.

 

The Spinning of Look AHEAD

March 17th, 2014

The Spinning of Look AHEAD

On January 13, 2014 the Obesity Society issued a press release1 proclaiming, “Largest U.S. Weight-Loss Study Shows Long-Term Weight Control is Possible with Intensive Weight Lifestyle Intervention (ILI) Eight-year Look AHEAD Results Show 50% of Participants Kept Off 5% or More of Initial Weight Lost.” The subjects of the press release are an article2 by the Look AHEAD Research Group (LARG) which describes the weight loss occurring among subjects in the federally-funded Look AHEAD trial which was prematurely ended for “futility” in 2012 and an accompanying editorial by Michael G. Perri.3

The release states, “The largest United States weight-loss study using diet and exercise alone shows long-term weight loss is possible through intensive lifestyle intervention (ILI) for weight management…Researchers found that ILI produced clinically meaningful weight loss (>5%) over eight years in half of the individuals and believe the intervention can be used for long-term management of obesity-related co-morbid conditions.

The release continues, “Although some weight regain occurred in this study, Look AHEAD’s 8-year trial results stand in contrast to this prior research, with study participants maintaining more than half of their weight loss after 8 years. Further, nearly 40% of participants who lost >10% of initial weight at year 1 maintained this loss at year 8….In addition, weight losses were similar among men and women and across racial-ethnic subgroups indicating that all individuals can benefit from an intensive diet and exercise intervention.” The release quotes with approval Perri’s editorial which states, “The success is likely due to the intensive and comprehensive nature of the lifestyle intervention, and confidence in the study’s findings is underscored by the trial’s excellent rate of retention.

Sounds good but is it accurate?  Let’s take a ‘deep-dive’ into the Look AHEAD trial.

Look AHEAD was a very important clinical trial, maybe one of the most important clinical trials given the prevalence of obesity and type 2 diabetes. With the increases in overweight and obesity not only in the United States but globally, type 2 diabetes is also increasing. Globally, the population with diabetes is expected to double between 2000 and 2030, based on demographic changes, especially the growth in the population over 65 years of age. 4 With type 2 diabetes, there is a risk of progression to cardiovascular disease (CVD) and death. About 2/3 of those with diabetes have CVD as the cause of death.5

While an earlier study6 showed that bariatric surgery could cause enough weight loss to lower rates of myocardial infarction, it had not been demonstrated that less weight loss from behavioral interventions could obtain the same effect. The implications for future development of type 2 diabetes and CVD is significant. A 2013 study found that all of the traditional risks factors for CVD in the diabetic population were improving over the last decade, with the exception of Body Mass Index (BMI) and waist circumference.7 (Body Mass Index is a frequently used measure of body weight and is calculated by dividing weight in kilograms by height in meters squared.)

In the words of the Look Ahead Research Group (hereafter “LARG”), “The purpose of the Look AHEAD trial is to determine whether cardiovascular morbidity and mortality in persons with Type 2 Diabetes can be reduced through an intensive lifestyle intervention aimed at producing and maintaining weight loss. Briefly the intensive lifestyle intervention (I call it über intensive lifestyle intervention, below) includes moderate-intensity physical activity to achieve and sustain at least 200 minutes per week of exercise together with a healthy diet that includes portion-controlled foods. The goal of this intervention is for individuals to achieve and maintain at least 10% loss of body weight. Failure to meet appropriate goals is followed by the option of initiating other ‘toolbox strategies (e.g. medication for weight loss).”8

Look AHEAD was a randomized clinical trial, implemented at 16 centers, involving 5,145 participants with half randomized to the Intensive Lifestyle Intervention (ILI) arm and half to Diabetes Support and Education (DSE) arm which is standard of care for patients with Type 2 Diabetes. According to Wadden et al, “In year 1, participants in this (ILI) group were provided a comprehensive intervention, designed to induce an average loss >7% of initial weight. Individuals were given the goal of losing >10% in order to increase their likelihood of meeting the 7% study-wide goal.9 (Emphasis added.) The primary endpoint of the study was a reduction in the incidence rate of a combination of cardiovascular death (fatal myocardial infarction and stroke), non-fatal myocardial infarction, non-fatal stroke and hospitalization for angina. Secondary endpoints included cardiovascular disease risk factors, diabetes control and complications, general health, hospitalizations, quality of life and psychological outcomes, cost and cost effectiveness.

According to the recent LARG report in the New England Journal of Medicine (NEJM)10, weight loss was greater in the ILI group than in the DSE (control) group. The ILI produced greater reductions in HbA1C and improvements in fitness and all CVD risk factors except for low HDL. The primary outcome (CVD events and death) was nearly identical in both groups. The NEJM article reports a mean weight loss in the ILI of 8.5% of initial body weight at year one and an average weight loss of 6% by the end of the trial. The DSE group lost very little in the first year but, at the end of the trial, had lost 3.5% of initial body weight. In other words, the mean difference between the two groups was only 2.5%, below the level considered “clinically significant.” Although not specified in either the NEJM or Obesity articles, a simple calculation shows that the ILI arm mean, placebo-adjusted, weight loss at the end of the study was all of 5.7 pounds, reducing the mean BMI by 0.8, from an estimated 35.8 to 34.9, still in the obesity category.11

As the trial showed that ILI could not reduce the rate of CVD events, it was stopped by the National Institutes two years early for futility.12

Contrary to the press release, Look AHEAD did not use “diet and exercise alone.” According to the LARG paper describing the baseline characteristics, “This was a medicated population with a high frequency of medication use”.  At the outset, more than 80% of participants were taking one or more glucose lowering drugs. Metformin most frequently used 48%, 14% were on insulin, 47% on antidepressants 15.8% on diuretics, and 28.4% were taking antihypertensive medications. 50% were on lipid-lowering agents, primarily statins.8 High statin use, greater in the control group than in the ILI group, apparently resulted in far fewer deaths and cardiovascular events than was anticipated. This necessitated, in the second year, an adjustment in the age limits of recruitment and later, the addition of additional components to the definition of cardiovascular events.13 “Only about 350 participants in each arm were not on a diabetes medication.14

Look AHEAD specifically encouraged the use of one weight loss drug, orlistat, which is approved by the Food and Drug Administration. According to the Look AHEAD Counselor’s Manual, “Orlistat has been shown to significantly improve the induction and maintenance of weight loss. The use of orlistat is described in a separate chapter of the Lifestyle Counselor’s Manual; review it before discussing the medication with participants. Information is also provided on a video tape that can be shown to participants. (Orlistat costs approximately $100 a month (per patient) but is being donated to Look AHEAD by its manufacturer.)”15 (We do not know how many participants actually took orlistat or for how long.)

Another FDA-approved weight loss drug, sibutramine, was on the market for most of the trial but was not recommended by the Look AHEAD counselors. Medication decisions were made by the participant’s own personal physician. Herbal weight loss product usage was not tracked.

According to the study published in Obesity, 76 participants in ILI and 84 in the DSE group had bariatric surgery. The weight loss from those who had surgery was not counted in the final tallies.2

It’s hard to see Look AHEAD as a “weight loss trial” per se. The trial did not compare diet to physical activity, or diet and exercise to weight loss drugs, or lifestyle intervention to bariatric surgery or low-fat to low-carbohydrate diet. DSE is not considered a weight loss program. Clinical trials are evaluated according to whether they met their primary and/or secondary endpoints. Weight loss was neither a primary or secondary endpoint.

The TOS press release states,  ”weight losses were similar among men and women and across racial-ethnic subgroups indicating that all individuals can benefit from an intensive diet and exercise intervention.” 1 Two things are wrong with this sentence: One, the participants were not typical of the whole population. Two, the Intensive Lifestyle Intervention was really an “Über-Intensive Lifestyle Intervention” where the participants received, for free, individual and group sessions, meal replacements, gym memberships, personal trainers and a $100 honorarium for the annual weigh-in.

The Participants

Only one in five of the individuals screened (5,145 out of27,000) were selected largely because they met the physical activity and motivational characteristics considered necessary to  achieve the 10% initial and 7% final weight losses.8 Participants in Look AHEAD were recruited with the expectation that they could meet these metrics: Lose 10% of body weight and maintain the loss, change dietary intake: 1200-1500kcal/day if <250 lbs,, 1500-1800 kcal/day > 250 lbs, and  < 30% calories from fat. They were expected to gradually increase their physical activity to 200 minutes a week. Participants were to keep daily records of their food intake, physical activity and other behaviors. 88.9% of the women and 86.2% of the men in the study had at least one prior intentional weight loss of greater than 5%.16

As part of the screening, participants had to pass the Graded Exercise Test. According to Brancati, “The Graded Exercise Test (GXT) excluded participants most likely to develop CVD events: The study included GXT as an inclusion criterion based on concerns about safety and liability related to initiating an exercise program in adults with type 2 diabetes at high risk for CVD. The GXT effectively excluded some higher-risk patients (e.g. those with prevalent symptomatic CVD) who demonstrated electrocardiographic or blood pressure abnormalities during the test. The prospect of XT may have also discouraged some individuals with exercise-induced symptoms from attempting to enroll in the trial.13 Eleven percent of those taking the GXT were excluded from the trial.17 Ribisi et all agreed, “ Look AHEAD had a graded exercise test and excluded the very unfit and those with a limited ability to sustain a regular exercise program which was a major segment of the intervention…The results of this study many not be representative of all individuals with type 2 diabetes in this age range because of specific inclusion/exclusion criteria. Since only overweight/obese individuals were included, this will bias the trend toward greater comorbidities and lower fitness than would be expected. Conversely, each participant also had to meet a minimum fitness level of 4.0 MET, which excluded the very unfit and those with a limited ability to sustain a regular exercise routine, which was a major aspect of the subsequent behavioral intervention.”18

Participants were healthier than expected. Look Ahead was not a cohort study where some 50% of eligible individuals in a community are enrolled. This was a type of trial which “typically forgo representativeness in favor of motivation to participate fully in study interventions”.13 “Overall, they (the participants) are healthier than diabetic individuals in the National Health and Nutrition Examination Survey with regard to glucose, HbA1C, and lipid levels and are less likely to smoke.”19

Study participants were required to participate in a 2-week run-in period that included successful monitoring of diet and physical activity. Look Ahead participants had a high usage of weight control practices at the outset. About 60% used increasing fruit and vegetable consumption, cutting sweets and junk food, and eating less carbohydrate foods. 41% reported self-weighing at least once a week.16

Can the results be generalizable to the entire population as the TOS press release states? The commentators say no. Perri’s accompanying editorial states, “ it is unknown whether the patterns of long-term weight changes observed by Look AHEAD are generalizable to younger adults (ages 21-44 years) and to individuals who do not have diabetes.”3 The LARG wrote in the NEJM paper, “We recruited patients with type 2 diabetes who were motivated to lose weight through lifestyle intervention and who could successfully complete a maximal fitness test at baseline. Thus, the results cannot be generalizable to all patients with type 2 diabetes.”10 A leading researcher in Look AHEAD, Dr. Rena Wing, told the FDA Advisory Committee, (referring to both the Look AHEAD trial and the Diabetes Prevention Program), “these are efficacy trials, not effectiveness trials, so that we are trying to select a group of participants appropriate for efficacy trials.”20 Efficacy trials are designed to see if the intervention has the desired effect, “does more good than harm under optimum conditions”. “Effectiveness” trials, on the other hand, are designed to see if the intervention works under real-world conditions, i.e. does the patient get better in typical usage.22

 

The Über-Intensive Lifestyle Intervention

The Centers for Medicare and Medicaid Services decided in 2012, following a recommendation from the US Preventive Services Task Force to cover, for Medicare beneficiaries, intensive behavioral counseling for adult obesity. Coverage is limited up to 21 visits a year.23 The Look AHEAD trial ILI arm is vastly more “intense”.

For the first year, participants were urged to attend up to twice (42) the meetings than Medicare covers.  After year 1, participants were encouraged to attend 2 visits per month year to end of the trial or up to 224 for the duration. The visits included group and individuals sessions. This was augmented by a second contact by phone or email. Participants were paid a $100 honorarium for attendance at annual weigh-ins.24

As noted above, the weight-loss drug orlistat was provided at no charge to those not reaching their weight loss goal. Meal replacements were also provided at no charge for the first 4 months with participants encouraged to replace two meals and one snack daily with liquid shakes and meal bars (up to 120 meal replacements. Gym memberships, personal trainers, rented home-exercise equipment, a more intensive diet option or clothing were also available at no charge up to $100 a month to the participants if they lost less than 5% of their initial body weight. 25 During years 2-8, all sites  offered monthly group meetings, one Refresher Group and one National Campaign, challenging participants to reach a specific goal for which they would receive a prize. Those providing the counseling included registered dieticians, psychologists, exercise therapists, all of whom were certified. These personnel were trained in cognitive behavioral therapy, and incorporated elements of problem-solving, motivational interviewing, and cultural tailoring.

The Uber-Intensive Lifestyle Intervention was committed to create a strong rapport between the staff and participants. This was true for the DSE participants as well but not for weight loss but retention in the group analysis. According to the LARG, “The DSE Committee worked under the premise that if the DSEI participants had a ‘perceived benefit’ from these sessions and formed a closer bond with the study staff, their commitment would be strengthened and retention in annual outcome assessments would be enhanced. However, from the study perceptive, a key aim was to produce a difference in weight and fitness between the participants in the two study arms; a goal which was achieved after 1 year.” 26

The Outcomes of Look AHEAD

Look AHEAD did not meet its primary nor secondary endpoints. While weight loss was greater in the Über-Intensive Lifestyle Intervention group than in the DSE group, this did not translate into a reduction the rate of cardiovascular events. 15.6% of participants in U-ILI and 16.2% in DSE died or had one of the specified cardiovascular events.11

14% of participants in U-ILI gained above their baseline weight. 32% of the U-ILI group did not lose at least 5% of initial weight in the first year (the most intense) and just over one-third (34.5%) of these individuals achieved this goal by year 8.3

The U-ILI group failed to meet 10% weight loss goal in first year and 7% goal by the end of the trial. The four year report9 included the percentages reaching the 7% goal but the eight year report did not provide the 7% figure. The TOS press release, Obesity article and editorial all indicate that these results provide hope for managing the comorbidities of obesity. A key indicator are reductions in medications and the start of the use of insulin but the eight year report2 did not include these factors. Hopefully, subsequent publications will report on these factors.

Overall, the U-ILI group lost 4.7% of initial body weight, the DSE group 2.1%, the differential (2.6%) being barely one BMI unit.

How does a 4.7% loss of initial body weight compare to alternatives?

According to Bray27, eliminating the placebo-adjusted calculation, weight-loss drugs such as phentermine showed a -6.4% annual reduction in initial body weight,  orlistat a -6.5% reduction, lorcaserin a  -10.2% reduction. For bariatric surgery, at 3 years post-surgery, the percent weight loss for participants who underwent Roux-en-Y-Gastric Bypass surgery from baseline was 31.5% and 15.9% weight loss from baseline for Laparoscopic Adjustable Gastric Band in the NIH-funded LABS study.28 An evaluation of a combined health professional-commercial weight loss program in the United Kingdom examined outcomes of a 12 week program by four BMI categories, 30 <, 31-34.9, 35-39.9 and 40>. Percent loss from initial body weight was 3.7%, 4.0%, 4.0% and 3.9%, respectively.29

Nevertheless, the Obesity editorial claims the reductions in 50% of the U-ILI group are a great success, and “likely due to the intensive and comprehensive nature of the lifestyle intervention.” Was the intensive and comprehensive nature of the lifestyle intervention also responsible for the other 50% that did not achieve a 5% reduction in body weight? Can one own the successes and not the failures? The editorial goes on to state that confidence is gained by the study’s high retention rate. It should be kept in mind that the retention rate refers to those who came in for their $100 check at the annual weigh-in. It should not be confused with adherence to the recommended dietary and physical activity recommendations. As Dr. Wing told the FDA Advisory Committee, “in other words, 95 percent are coming to the (annual) visits, but clearly, many of them are not adhering to the diet and exercise prescription.” 30

What are implications for future obesity treatment?

What are the clinical implications? Should über- or intensive or simple lifestyle changes be recommended as the first line treatment when they offer so little? Is holding out intensive or simple lifestyle change only providing “false hope” to those living with overweight and obesity?

It seems the overweight and obese persons with type 2 diabetes should go on lipid-lowering products as soon as possible. Their high usage in the DSE group caused a remarkable drop in the expected cardiovascular event rate.

Second, regarding sub-groups, in this trial (as with the Diabetes Prevention Program) the most improvement is seen in the older populations. There are a variety of reasons for this, including more time to devote to the dietary, higher health care concerns and physical activity  but it may also have been due to aging, and other health problems. The progressive loss of muscle and gain in fat (sarcopenia obesity) may complicate treatments for this group.5

Third, there is a very interesting trajectory in the two groups. The U-ILI group lost most of their weight in the first year and gradually regained. The DSE group lost very little in the first year but have seen regular improvements in weight loss since then. The loss is less than considered clinically meaningful but the differences between the two groups is interesting. The Obesity paper acknowledges that the DSE participants could have intentionally lost weight or it could be due to unintentional activity, aging or diabetes (which, of course, would also be true of the U-ILI group).

The NEJM article states that this study represents that the “weight loss achieved in the intervention group is representative of the best that can be achieved by current lifestyle approaches”10. If so, it’s a pretty meager showing for a highly-motivated population receiving an Über-Intensive-Lifestyle Intervention. These results should be the starting point for a broad re-assessment of behavioral lifestyle interventions (whether über-, or intensive or moderate intensity). A ‘scientific society’ should confront the data and lead the discussion for re-assessment instead of putting the proverbial lipstick on a pig.

FOOTNOTES

  1. http://www.obesity.org/news-center/look-ahead-8-year-results.htm, accessed March 17, 2014.
  2. Look AHEAD Research Group, Weight Losses with an Intensive Lifestyle Intervention: The Look AHEAD Study, Obesity (2014), 22, 5-13, PubMed.
  3. Perri MG, Effects of behavioral treatment on long-term weight loss: Lessons learned from the Look AHEAD trial. Obesity 2014 Jan:22(1):3-4 Pub Med.
  4. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030, Diabetes Res Clin Pract 2011 Dec;943:311-21 PubMed
  5. Cetin DC, Nasr G, Obesity in the elderly: More complicated than you think. Clev Cl J Med 81(1) 2014:51-61 PubMed
  6. Sjöström, et al, Effects of Bariatric Surgery on mortality, NEJM 2007 Aug 23;357(8):741-52 PubMed
  7. Wong ND, et al, Trends in cardiovascular risk factor among US adults with type 2 diabetes from 1999 to 2010: Comparison by prevalent cardiovascular disease status, Diab Vasc Dis Res 2013 Nov;10(6):505-13. PubMed
  8. LARG, Baseline Characteristics of the randomized cohort from the Look AHEAD (Action for Health in Diabetes) study, Diab Vasc Dis Res. 2006 Dec;3(3):202-15 PubMed
  9. Wadden TA, et al, Four-Year Weight Losses in the Look AHEAD Study: Factors Associated with Long-Term Success. Obesity 2011 Oct;19(10):1987-98 PubMed
  10. LARG, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes, NEJM 2013 Jul 11: 369(2):145-54 PubMed
  11. Calculation was Initial weight 100.54kg X 2.6% reduction = 2.6 kg = 5.7 lbs)
  12. NIH Press Release http://www.nih.gov/news/health/oct2012/niddk-19.htm, accessed Feb.13,2014.
  13. Brancati, FL et al, Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study, Clinical Trials, 2012; 9 (1):113-124 PubMed.
  14. Wing, R, Transcript, FDA Endocrinologic and Metabolic Drugs Advisory Committee, March 28, 2012 at p. 160, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303355.pdf, accessed Feb.13, 2014.
  15. Look AHEAD Counselor’s Manual. https://www.lookaheadtrial.org/public/dspMaterials.cfm, Ch. 25, p.7, accessed Feb. 13, 2014
  16. Raynor HA, et al, Weight loss strategies associated with BMI in overweight adults with type 2 diabetes at entry into the Look AHEAD Action for Health in Diabetes) trial, Diabetes Care 2008 Jul;31(7): 1299-304 PubMed
  17. Wing, op cit, at p. 176.
  18. Ribisi PM, et al, Exercise Capacity and Cardiovascular Characteristics of Overweight and Obese Individuals with  Type 2 Diabetes, Diabetes Care 2007 Oct;3010):2679-84 PubMed
  19. LARG. Reduction in Weight and Cardiovascular Disease Risk Factors in Individuals with Type 2 Diabetes, Diabetes Care, 30(6):1374-1383. PubMed
  20. Wing, op cit, at p. 152.
  21. Wing, op cit, at p. 169.
  22. Glasgow, RE et al, Why Don’t We See More Translation of Health Promotion Research to Practice? Rethinking the Efficacy-to-Effectiveness Transition Am J Pub Health, 2003, Aug;93(8):1261-1267 PubMed.
  23. Centers for Medicare and Medicaid Services Decision Memo on Intensive Behavioral Counseling for adult obesity http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?&NcaName=Intensive%20Behavioral%20Therapy%20for%20Obesity&bc=ACAAAAAAIAAA&NCAId=253&, accessed February 15, 2014.
  24. Wing, op cit at p172.
  25. Look AHEAD Lifestyle Counselor’s Manual,  https://www.lookaheadtrial.org/public/dspMaterials.cfm, Ch. 25, p. 7, accessed Feb. 15, 2014.
  26. Wesche-Thobaben, LARG, The Development and description of the comparison group in the Look AHEAD trial, Clinical Trials 2011, 8:320-329, PubMed.
  27. Bray, GA, Why do we need drugs to treat the patient with obesity? Obesity, 2013 May; 21(5):893-9. PubMed.
  28. Courcoulas AP et al, Weight Change and Health Outcomes at 3 years After Bariatric Surgery Among Individuals with Severe Obesity JAMA 2013;310(22):2416-2425. PubMed.
  29. Stubbs, RL, et al, Service evaluation of weight outcomes as a function of initial BMI in 34,271 adults referred to a primary care/commercial weight management partnership scheme. BMC Research Notes 2013, Apr 24;6: 161. PubMed.
  30. Wing, op cit. at p. 172.

 

 

 

 

 

 

 

Results of Look Ahead Published

June 26th, 2013

As indicated on October 22, 2012, the Look Ahead trial was stopped early on the basis of futility. Now, we have the results of the study in the New England Journal of Medicine, June 25, 2013. The trial was a long-term study of intensive lifestyle intervention for weight loss to see if that would decrease cardiovascular morbidity and mortality among patients with type 2 diabetics. After 9.6 years, the study was stopped. While weight loss was greater in the intervention group than in the control group (6.0% v. 3.5% at study end), the intensive weight loss did not reduce the rate of cardiovascular events. The lifestyle intervention did reduce HbA1c, improve fitness and all cardiovascular risk factors except for low-density lipoprotein cholesterol levels. In addition, earlier reports indicated that the lifestyle group was more likely to have a partial remission of diabetes during the first 4 years of the trail than those in the control group and also showed reductions in urinary incontinence, sleep apnea, and depression and improvements in quality of life, physical functioning and mobility.

 

Patterns of Weight Loss in Look AHEAD

December 5th, 2012

While the Look AHEAD trial has been suspended,  it much information to yet give up.  In a paper in Obesity, the Look AHEAD Research Group reports that 2 components of the Look AHEAD program accounted for about 95% of the total variability in weight loss patterns. They looked at two patterns of weight loss. The first is a relative large, early weight loss, followed by long period of maintenance. The second pattern is a more gradual, slower weight loss over a longer period of time.  They found that participants with greater month-to-month weight losses during year 1 had significantly better levels of HbAc and HDL-cholesterol at year 4, even after controlling for medications. Gradual weight loss produced better weight loss maintenance but no additional benefits. The paper did not link weight loss with specific strategies used in the interventions in Look AHEAD nor did it look at the genetic factors.    PubMed: Patterns of Weight Change in Look AHEAD Study

 

Diabetes Rates Soar

November 28th, 2012

The Center for Disease Control and Prevention (CDC) has reported that the prevalence of diagnosed diabetes has increased in all US states, the District of Columbia and Puerto Rico between 1995 and 2010. The prevalence increased by 50% or more in 42 states and by 100% or more in 18 states. The states with the largest increases were Oklahoma, Kentucky, Georgia, Alabama and Washington. According to the CDC press release, in 1995 only 3 states had diagnosed diabetes prevalence of 6% or more; by 2010, all 50 states had a prevalence over 6%.

The press release, (rather amazingly to my point of view) states, “Type 2 diabetes, which may be prevented through lifestyle changes, accounts for 90 percent to 95 percent of all diabetes cases in the United States. CDC and its partners are working on a variety of initiatives to prevent type 2 diabetes and to reduce complications in those already diagnosed. CDC leads the National Diabetes Prevention Program, a public-private partnership that brings evidence-based programs for preventing type 2 diabetes to communities. The program is helping to establish a network of lifestyle-change classes for overweight or obese people at high risk of developing type 2 diabetes.” Of course the evidence-based program they refer to are the Diabetes Prevention Program, which found lifestyle prevention was only effective in young retirees and the Look AHEAD trial, which was terminated prematurely because the lifestyle group had no better outcomes than the control group. Why does the CDC continue to hype bang-the- lifestyle-drum when they know it doesn’t work?

 

Look AHEAD Crashes

October 22nd, 2012

 

Behind Look Ahead

The National Institutes of Health (NIH) has announced that the Look AHEAD trial has been stopped in its 11th year, two years short of completion. The extensive trial, involving over 5,000 patients at 16 centers, was intended to find out if there was increased mortality from intentional weight loss and to see if intentional weight loss among obese patients with type 2 diabetes would result in fewer cardiovascular (CV) events. At the end of the trial, there was no difference between the study group, which received intensive behavioral counseling and the control group which received standard diabetes education and occasional support group meetings.  The NIH press release indicates that both arms had lower CV rates that reported for patients with diabetes in previous studies. NIHNEWS: Weight Loss Not Reduce CV events in Type 2 diabetes

While this is news is something of a shock, many folks saw it coming. Two years into the trial, which began in 2001, the monitoring board noticed that the event rate in the control arm was much lower than expected. The expected CVD event rate in the control arm was 3.125% per year; in fact it was 0.7%. A committee was formed and made changes to the original study protocol designed to capture more events. These changes went into effect in 2008. There appeared to be three reasons for the lower event rate. First, while cardiovascular disease (CVD) is still the major cause of death in the United States, mortality has gone down, resulting from better control of dyslipidemia and high blood pressure and improved care of chronic and acute coronary syndromes. (See NCHS Data Brief, NCHS DataBrief: Prevalence of Uncontrolled Risk Factors for CVD)  Second, study participants who choose to involve themselves in a long clinical trial may well be healthier than a community sample and more motivated to follow the diet and exercise and participation requirements. Finally, the Look AHEAD trial employed the Graded Exercise Test which excluded participants most likely to develop CVD. Because of the low event rate, an additional primary endpoint was added (hospitalized angina) and the trial was extended for 2 years. (See PubMed: Brancati_Midcourse Correction to clinical trial whe the event rate is underestimated: the Look Ahead Study) Readers may recall that the SCOUT trial of sibutramine also had to revise its protocol midway through the study for the same reason, resulting in a population which was older and sicker than typical clinical population. In both cases, revising the protocol did not favor the intervention.

The stopping of Look AHEAD raises a host of questions. Was the study protocol correct? Did it end up studying healthy obese diabetics? Do long-term studies produce more noise than insight? Are we really studying the aging process when we cannot control for changes in health status, drug utilization (including drugs which can increase weight) and changes in energy intake, fitness levels, etc.? What is the picture for sub-groups, such as the 60-74 age group which had good weight loss in the DPP and 4 year results of Look AHEAD? Were there specific improvements, such as reductions in medications usage, fewer hospitalizations or shorter length of stays, improvements in quality of life? Did the presence of any the alleles associated with success in bariatric surgery affect outcomes? PubMed: High allelic burden of four obesity SNPs associated with poorer wt loss.  Should future efforts be devoted to cases where the disease process is already well-established or where high-risk populations can be identified and appropriate interventions evaluated? In future trials, should comorbid management be left to the local standards of care or defined in the study protocol?

Looking Ahead of Look Ahead

Whither behavioral lifestyle interventions?

The lifestyle interventions in the DPP and Look AHEAD were regarded as the ‘gold standard.’ They involved recruiting and training health professionals who provided not only the intervention but provided a supportive environment and a community spirit. Extensive communication with the patient was maintained. PUBMED: Look AHEAD: Description of the Lifestyle Intervention. Look AHEAD  participants even received an honoraria of $100 at each annual visit to improve adherence. (FDA EMDAC Hearing, March 28, 2012, Dr. Rena Wing, transcript, p. 169).

Recently the CDC and the NIH were looking at ways to take the DPP/Look AHEAD model to a more replicable model. The CDC’s National DPP program awarded $6.75 million in grants to develop lifestyle interventions program among people at high risk. One involves using the YMCA to provide lifestyle counseling. http://www.ymca.net/diabetes-prevention/ Questions will certainly be asked if highly trained professionals with incentives for participants did not produce better results will a down-scale program do better?

Whither diabetes prevention?

Look AHEAD was designed following the Diabetes Prevention Program (DPP). The DPP established that both lifestyle changes and metformin could reduce the incidence of type 2 diabetes, through weight loss, although lifestyle was superior to metformin alone. Look AHEAD was taking this important finding one step further asking whether weight loss among type 2 diabetics would reduce the incidence of cardiovascular events.

Even though the DPP has been promoted as a model for preventing the development of type 2 diabetes through weight loss, there were problems.

Dr. William Knowler of the National Institute on Diabetes, Digestive, and Kidney Disease (NIDDK) told the FDA Advisory Committee earlier this year,that, after three years of the DPP,

“the rates (of development of type 2 diabetes) have tended to flatten out and become parallel among all three groups. The rate of new development of diabetes has actually slowed down in the placebo and metformin groups, compared to what it was in the first three years. And the lifestyle group has flattened out a little bit at the end, but the difference that was attained has been largely maintained over time.  Notice, though, that over 10 years, although there still are remarkable treatment effects, if you look at things in an absolute sense, we can’t say that we still know how to prevent diabetes because, still, close to half of the people who enrolled in the trial developed diabetes over a 10-year period. But at least it’s been substantially delayed in those who have had the interventions.” ( FDA Endocrinologic and Metabolic Drug Advisory Committee Hearing on assessing cardiovascular safety of obesity drugs, March 28, 2012, Transcript, p 131-2).


(Figure: Diabetes Prevention Program Outcomes Study, Lancet (2009) 374; 1677-1686)

Is ‘delaying’ diabetes onset as powerful as ‘preventing’ diabetes from occurring in the competitive race for health care dollars and public attention?

Furthermore, a study earlier this year indicate poor outcomes in drug treatment of adolescents with type 2 diabetes with barely half showing glycemic control with metformin. PubMed: Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes

Will the Look AHEAD experience affect FDA approval of drugs and devices to treat obesity?

The FDA has viewed obesity as a cosmetic issue and only recently acknowledged it as a disease, worthy of attention as other cardiovascular risk factors. They (meaning the FDA Endocrinologic and Metabolic Drug Advisory Committee and FDA staff) have started, just barely, to view obesity as a cardiovascular disease risk factor, like hypertension. They have also opined, from time to time, that if folks only ate less and exercised more, they would not need drugs. So how does this decision play into these views? On one hand, they may be convinced that obesity is not so easy to treat as they thought by diet and exercise. On the other hand, they may think that there is less need for anti-obesity medications because other treatments, e.g. statins, lipid-lowering drugs, anti-hypertensives, are doing their job in reducing CV risk factors. So, this view may raise the bar for approval of new anti-obesity medications. On the other (the third?) hand, we may need a re-definition of obesity which tones down its “diabetes-metabolic syndrome-mortality” axis and raises its “disability-mobility-quality of life” axis. (Running out of hands here, I would not underestimate the potential for greater evidence of obesity’s role in the development of various cancers).

The recent trend in thinking at the FDA Endocrinologic and Metabolic Drug Advisory Committee (EMDAC) has been to view anti-obesity medications narrowly as cardiovascular disease treatments. The EMDAC met on March 28th and 29th,2012  and discussed how to assess the cardiovascular benefits and safety of anti-obesity medications. At the end of March 28, Dr. Rasmussen, who is the Industry Representative on the committee had the following exchange with Dr. Eric Coleman of the FDA.

Dr. Rasmussen: In your (Dr. Colman’s) presentation, you showed that there are different            populations pre-approval and in post-approval studies. ..Are we compromising the risk-            benefit evaluation if we impose more risk-based patients pre-approval?

Dr. Colman: I’m not sure I understood your question. Could you rephrase it?

Dr. Rasmussen: Maybe I’m preempting some of the discussion that we’ll be having                        tomorrow, whether we should require more high-risk CV patients pre-approval to rule out        a upper bound of the 95 percent confidence interval. But by doing so, we will likely be                including older patients with established cardiovascular risk disease. And I’m wondering          whether including more of those types of patients will compromise the benefits side of                doing the benefit-risk evaluation.

Dr. Coleman: Yes. And it might be that if the program had the resources to do this, that              that would just be one component of the program, and that there would be other be other,        smaller, shorter-term studies where they could study lower-risk individuals, younger                   individuals for shorter periods of time.

Dr. Rasmussen: But my concern was based on the fact that the SCOUT study didn’t really – I      mean, it looks like it wouldn’t be actually be able to be approved if it was submitted pre-            approval. ..(FDA EMDAC, March 28, 2012, transcript at p. 334-5)

On the second day of the hearing, Dr. Rasmussen returned to the topic.

Dr. Rasmussen: So I would just like to add a little bit of perspective on what “enrichment”          (Editor: “enrichment” is the term used here by the FDA referring to adding persons at high        risk of CVD to the pool of subjects in obesity drug trials) in this context will mean. I mean, I      did a little bit of “back-of-the-envelope” calculation, and maybe we’ll have that confirmed        after lunch. But, I mean, current programs, approximately 3,000 patient-years of                        exposure generate 15 MACE events or so. Even if we were to double that patient-year                  exposure with a population of a 3-percent annual event rate coming to additional 60                    events, we would still only be able to exclude a doubling of the hazard ratio. So, I mean,              what we’re talking about here is actually completely shifting the population that we’re                going to study in obesity programs to establish cardiovascular disease and not necessarily        the population that we know actually seek treatment in the real world. So, I think that’s              worth keeping in mind, that enrichment may sound appealing because it sounds like we will       add a fraction of sick patients, but in reality, this will be a complete shift of the population.        (FDA, EMDAC, March 29, 2012, at p. 169)

(Dr. Rasmussen’s calculations appear correction. The cardiovascular safety trial the FDA asked Orexigen Therapeutics to undertake surpassed its original goal of 7,000 patients in process of enrolling 9,000 patients to find 87 major CV events earlier than expected. Orexigen: Press Release Contrave CV study.)

A bit later, Dr. Rena Wing was asked about the influence of statins on the Look AHEAD trial. She responded:

Number one, that more and more people are being treated with statins. There’s better                blood sugar control. There’s better hypertension control. So you’re going to have to look          at what’s going to happen to the event rates in these studies. I was very surprised that your      event rates that you’re showing me in many of these trials looked so high compared to the        event rates we’re seeing in Look AHEAD. Now, some of that is because we did do GXTs.                (Editor: Graded Exercise Tests.) We did select healthier patients. But I also think that if you      are doing trials, in the United States especially, and with diabetics where there’s more and        more emphasis on increasing the use of lipids, increasing their blood pressure control, that      you’re going to be driving down your risk factors, and you’re going to have more and more      confounds with medication. (FDA, EMDAC, March 29, 2012 transcript, at p. 346)

At the Cleveland Clinic’s Obesity Summit earlier this month, I asked cardiologist Steve Nissen about the FDA’s pushing companies to undertake clinical trials to rule out a CVD risk. He responded that one of the challenges of cardiovascular outcome studies of obesity drugs is that in order to get enough cv events you have to study patients with existing heart disease or at very high risk of a cv event . This pushes the trial into populations which are considerably sicker than the population likely to take the obesity drug. He suggested that FDA should look at absolute risk rather than the relative risk of the drug. If one looks at the absolute risk, you can study any reasonable population likely to take the drug. This change in the statistical approach allows one to study more typical populations.

 

In any event, it will be sometime before we know how the newer anti-obesity medications, like Contrave if approved), Belviq™ and Qysemia™ will impact cardiovascular disease risk factors.

Bariatric Surgery: Last Man Standing?

A study out of the Cleveland Clinic published in the New England Journal of Medicine in April, 2012 followed over 90% of 150 patients for 12 months. The study, a face to face comparison of medical therapy versus surgery in patients with uncontrolled type 2 diabetes, showed a clear superiority for bariatric surgery.  The proportion of patients achieving a hemoglobin A1c level of 6% after 12 months by medical therapy alone was 12%; for those in the medical plus gastric bypass surgical group it was 42% and for the medical plus sleeve-gastrectomy group it was 37%. Weight loss was greater in the gastric bypass group (-24kg) and sleeve gastretcomy group (-25.1kg) than in the medical therapy group (-5.4kg). Use of drugs for glucose control, lipids and blood pressure control decreased in the surgical group but increased in the medical group. PubMed: Bariatric surgery versus intensive medical therapy in obese patients with diabetes

In regard to cardiovascular risk factors, a systematic review of the literature on bariatric surgery analyzed over 60 studies involving 19,543 patients. At baseline, the mean patient was 41.7 years old, female and had a BMI of 47.1. Baseline prevalence of comorbid conditions which increase risk of CVD was hypertension (44.4%), diabetes (24%) and hyperlipidemia (43.6%). After correcting for publication bias, 36% of subjects had improvements in hypertension, 26% for diabetes and 34% for hyperlipidemia. Calculating the changes for mean participants, the authors found that a woman, without baseline CVD, diabetes or smoking, who is taking anti-hypertensive drugs, will move from an 8.6% 10 year global risk for CVD to a 3.9% risk. A man, with no CVD or smoking but whose diabetes and need for anti-hypertensive drugs resolves after surgery, will move from a 10 year global risk of 18.4% to 4.7%. PubMed: Bariatric Surgery and Cardiovascular outcomes: a systematic review

So, where are we? The gold standard of lifestyle change is tarnished. The drug story is muddy at best. Bariatric surgery is clearly producing the superior results. However, access to surgery is, and will remain, a problem. The challenge for the leaders in the field is to find ways to have surgery reach more people and not be a procedure for the 1 percent. Even with greater access to surgery, the obesity-diabetes epidemic will continue to be a major health crisis. It’s time to be humble in the face of this disease and realize a lot more research is going to be needed…and soon.

 

Genetic Variations Affect Weight Loss, Regain, Eating Behavior

May 1st, 2012

The Diabetes Prevention Program (DPP) is a highly publicized study comparing lifestyle intervention against metformin in preventing type 2 diabetes. It has been widely used by public health authorities to promote lifestyle changes over drugs in addressing obesity and type 2 diabetes. Delahanty LM and colleagues looked at genetic polymorphisms for an effect on short term and long term weight loss and weight regain. They found that the Ala allele at PPARG (think of this as the longitude and latitude for a gene variation) was associated with short term and long term – weight loss regardless of treatment. This study adds to the literature that genetic information can help identify those who can are more likely or less likely to benefit from intervention. PubMed:Genetic Predictors of weight loss, regain DPP

In a another trial, Look AHEAD, another obesity related risk allele at FTO rs1421085 significantly predicted more eating episodes per day. Variants within BDNF were significantly associated with more servings of dairy, meat, eggs, nut and beans. Another allele was associated with a significantly lower percentage of energy from protein. PubMed:Genetic alleles and dietary intake in Look AHEAD trial