Archive for October, 2012

Gallup: Obesity Increases In All Age Groups

October 24th, 2012

The Gallup survey has reported that obesity has increased in every age group in the United States from 2008 to 2012. The Gallup-Healthways Well-Being Index tracts health indicators. This survey showed significant increases in obesity among the elderly. It points to a steady pattern of weight gain through adulthood with decreases only in the 70s. “Most Americans who are over the age of 35 are now significantly more likely to be obese than those who were that same age four years ago, “ according to the report. GallupPoll: Obesity Increases in Every Age Group

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. 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.


Beverage Industry Buys In to PAHO

October 20th, 2012

Reuters, which had a highly critical report on Michelle Obama’s child obesity campaign, has now revealed that the Pan American Health Organization (PAHO), a regional office of the World Health Organization (WHO)  has taken funds from food and beverage companies implicated in the obesity epidemic, contrary to WHO guidelines. PAHO did not begin to take industry money until this February but since then has received $50,000 from Coca-Cola, $150,000 from Nestle, and $150,00 from Unilever. Reuters reports that WHO has cut its own funding for chronic disease programs by 20% since 2010. While chronic diseases cause 63% of premature deaths worldwide, the WHO department to fight them receives 6% of the agency budget, forcing them into “partnerships” with the food and beverage industry. An arm of PAHO, the Pan American Forum touts the benefits of membership as helping businesses avoid regulation and influence regulatory environments. Reuters: Special Report: Food, Beverage Industry Pay for Seat at the Health Policy Table.

The Obesity Paradox

October 20th, 2012

The Obesity Paradox refers to the phenomenon that obesity appears to be protective after an initial heart attack. (Some researchers believe that the inaccuracies in the BMI are responsible for the perceived differences PubMed: Body Composition and survival in stable coronary heart disease.)  Now comes a study from W. Doehner and colleagues at the Center for Stroke Research in Berlin, Germany. They found that the risk of mortality from a stroke or TIA was lower in overweight patients and lowest in obese patients compared to patients with a normal BMI. Obese patients had a lower risk of death or institutional care, death or high dependency, and death or recurrent stroke. Underweight patients had consistently the highest risks for all endpoints. PubMed: Overweight and obesity are associated with improved survival

The study from Germany did not evaluate consumption of dark chocolate. An UK study found consuming 20 grams of dark chocolate a day decreased systolic and diastolic blood pressure. PubMed: Differential effect of polyphenol-rick dark chocolate on biomarkers (Editor’s note: We need more studies like this!)


Most Obese States Drop Medicaid Expansion

October 17th, 2012

If you follow developments in obesity at all, you are familiar with the CDC maps showing the increases in obesity across the nation. Likewise, it is clear from these maps, the obesity is a major problem in the South.

Unfortunately, and tragically for many obese poor persons, the governors of Florida, Louisiana, Georgia, South Carolina and Texas have now been joined by the governor of Mississippi in rejecting the expansion of Medicaid in their states. The expansion is authorized under the Affordable Care Act (Obamacare). St.LouisPostDispatch_Mississippi Decides Medicaid Dollars not Worth Cost

Under the Affordable Care Act, the federal government will pay 100% of the cost of expanding Medicaid from 2014 to 2016. Between 2017 and 2020, the federal share drops to 90% and the states’ contribution gradually rises. The Kaiser Family Foundation projected that Mississippi would receive $23 dollars from Washington for every $1 from the state.

While state budgets are clearly under pressure, many see politics at work as all of the Governors in these states are Republicans and are opposed to Obamacare. Regardless, Mississippi has the highest rate of childhood obesity in the nation with nearly 40% of children up to age 17 meeting the obesity criteria. In all of these states, the lower income groups, who would be covered by the expansion of Medicaid, have major health problems. Refusing to participate in the Medicaid expansion only perpetuates these issues.


Lipid Levels Drop for US Adults

October 16th, 2012

Serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) contribute to atherosclerosis and its effects on heart health. An update on these lipid levels among American adults has just been published in JAMA. The paper by Margaret D Carroll and colleagues found that mean total cholesterol declined from 206 in 1988-1994 to 129. Mean HDL-C increased. Mean serum triglyceride levels increased from 118 in 1988-1994 to 123 in 1999-2002 and decreased to 110 in 2007-2010. The prevalence of lipid-lowering medication use increased from 3.4% in 1988-1994 to 15.5% in 2007-2010. Among adults not receiving lipid-lowering medications, trends in lipids were similar to those reported for adults overall. Among obese adults, mean TC, non–HDL-C, LDL-C, and mean triglycerides declined between 1988 and 2010. JAMA: Trends in Lipids and Lipoproteins in US Adults, 1988-2010


How reliable are parent-child surveys?

October 15th, 2012

A study out of Central Michigan University compared parent and child self-reports of diet, physical activity and screen time. What they found was that not one of the 88-dyads of parent-child reports matched up. Not one pairing was congruent on nutritional habits, juices, soft drinks, screen time or physical activity. PubMed: Parent and Child Self Reports of Dietary Behaviors, Physical Activity, Screen time

Life Expectancy and Physical Activity

October 15th, 2012

So how big an effect is physical inactivity? We hear all the time how terrible physical inactivity is but just how bad. Now comes an answer. Some 39 collaborators, part of the Lancet Physical Activity Series Working Group have published an analysis of the burden of physical inactivity on disease and life expectancy.

The researchers calculated population attributable fractions associated with physical inactivity “using conservative assumptions for each of the major non-communicable diseases by country, to estimate how much disease could be averted if physical inactivity were eliminated.”

They estimated that, worldwide, physical inactivity causes, for coronary heart disease, between 3.2% in southeast Asia to 7/8% in the eastern Mediterranean. For type 2 diabetes, physical inactivity contributes 7%, 10% of breast cancer and 10% of colon cancer. “Inactivity,” they calculate, “causes 9% or more of premature mortality or more than 5.3 million of the 57 million deaths that occurred worldwide in 2008. If physical inactivity were eliminated, life expectancy of the world’s population would increase by 0.68 years (range of 0.41-0.95).

That’s it? 8 months?  Well, that’s for both the active and inactive population. If you look at just having the physically inactive reach recommended levels of physical fitness, it is estimated that inactive people would gain 1.3 to 3.7 years from age 50 on in the United States. In East Asia, life expectancy from age 30 increased by 2.6 to 4.2 years. That’s a bit more meaningful. PubMed: Effect of physical inactivity on major non-communicable diseases worldwide