Medical Research and Groundbreaking Medicines in the Battle Against Obesity

Mecial Research and Groundbreaking Medicines in the Battle Against Obesity

Obesity is a major health problem in our country because of its high prevalence and its causal relationship with multiple, serious medical diseases.

There is no organ system in the body that isn’t adversely affected by excess body fat and it is the second most common cause of preventable death after smoking. Having a body mass index (BMI) of 30 or above constitutes obesity, but evaluating a person requires some clinical judgement in addition to BMI.

Obesity Research


Samuel Klein, MD, Division Chief, William H. Danforth Professor of Medicine and Nutritional Science shares there’s considerable heterogeneity in the relationship between obesity and its cardio-metabolic complications… heart disease, heart failure, pre-diabetes, diabetes, fatty liver disease, hypertension, dyslipidemia, and the reason for the heterogeneity is not clear. There are some people that are obese who are metabolically healthy, with normal blood sugar, normal insulin-sensitivity, normal blood lipids, etc. There are others who have the typical manifestations of obesity with all the metabolic complications. We don’t understand why some people are resistant to the adverse effects of excess body fat and other people are prone to develop the complications of excess body fat. “This is a key area of our research program to understand why excess body fat causes cardio-metabolic disease and cardio-metabolic dysfunction. And why some people seem to be protected from getting those complications. We are fortunate to be able to do this work at Washington University because of our outstanding faculty, trainees, and support staff and a sophisticated Clinical Translational Research Unit that allows us to do leading edge research in people.”

The second thing about obesity is it’s not clear why weight loss is so therapeutic and even a little weight loss can cause significant benefits but there’s also heterogeneity in the beneficial effect of weight loss in terms of the cardio-metabolic complications of obesity. Some people don’t improve with weight loss while others have considerable improvement in their cardio-metabolic function with weight loss.

Klein shares, “We still don’t understand fully the mechanisms for that. Studies that are done in rodents don’t always translate to people so we have an aggressive program in people to try to understand why excess body fat causes cardio-metabolic disease and why weight loss is so therapeutic. We know that simply removing body fat by liposuction, and we have evaluated the effect of removing a large amount of body fat by liposuction, does not improve cardio-metabolic outcomes.”

Samuel Klein, MD

To get the beneficial effects of fat reduction we have to eat less calories than we expend to experience the beneficial effects of weight loss.  Just removing fat surgically does not cause cardio-metabolic benefits.

Obesity is very difficult to treat because it is caused by an adverse interaction between our genes and our environment. Our genes have been programmed to eat food and store excess calories as body fat to survive periods of food deprivation and famine. In our current environment we have an excess amount of available foods, increased drivers to eat foods based on marketing, taste, preservation of food, and decreased energy expenditure because of labor saving devices, automobiles, and a decrease in physical activity. Our genes have not been able to adapt to the very rapid changes in our environment which has caused a marked increase in the prevalence of obesity not just in the US, but worldwide.

Managing Obesity

The management of obesity has typically been behavioral therapy to change lifestyle behaviors which is very difficult to do because they’re ingrained. For example we tell obese people to eat half the calories they typically eat. It’s very difficult to make those lifestyle changes which require more than just education; cognitive behavioral therapy, and being constantly vigilant is needed for long-term success. Many people who lose weight with lifestyle intervention regain their lost weight over time.  Fortunately, treatments for obesity have improved with longer duration of behavior therapy, endoscopic therapy and bariatric surgery, which is the most effective available therapy for obesity which can cause weight losses of 25 to 35% and maintain those long-term weight losses. We don’t understand why bariatric surgery works…but they cause people to eat less food and have a decreased desire to eat food.

Game-changing Medicines

The most recent development has been a game-changing development of medications that are effective in getting people to eat less food and lose weight. The results from these new medications are remarkable because they are effective in blocking the redundant metabolic and brain pathways that are responsible for stimulating food intake.

GLP-1s are a type of incretin mimetic, medications that affect gut hormones and cause weight loss.

GLP1 agonists have been a major breakthrough in the treatment of obesity and now these GLP1 agonist are being combined with other agonists, such as GIP. GIP-1 and GIIP are hormones released by the intestine after food consumption that affect many different metabolic pathways. The weight loss achieved with these medications is remarkable and demonstrate large and effective weight loss can be achieved with pharmacotherapy without serious side effects and safety risks. The major problem with these medications is that they are expensive and not readily available. As manufacturing facilities increase, we hope these medications will be more available and less costly so that more people can take advantage of their health potential medications. Nonetheless, we should also include behavior modification and lifestyle changes with these medications in order to maximize their beneficial effects and improve overall the health of our patients.

Diet and Exercise

Diet and exercise scale and hand weights.

We know that exercise and increased physical activity is not a very effective way to lose weight. The calories you burn during physical activity is minimal for most people who are obese and can be easily replenished with a single slice of pizza. However, exercise is very important for cardiometabolic health, namely fitness and insulin sensitivity, which are major causes of obesity’s adverse effects on health. We recently completed a study demonstrating that if you lose weight by diet plus physical activity you double the improvement in insulin sensitivity than if lost the same amount of weight by diet alone. Exercise is a critical component of people’s health and should consist of endurance exercise (e.g. walking, jogging, cycling) and resistance exercise (e.g. weight lifting and strength training) which will improve your cardiometabolic health and physical function.

Another important thing to know that even a small amount of weight loss can have important health benefits…even though the more you lose the better; about 15 to 25% provides major health benefits and is associated with remission of type 2 diabetes in many patients.

Losing a little bit of weight, which is much easier to achieve, has significant medical benefits and so it’s important we rethink about the management of people with obesity. Our treatment should be solely focused on changing body weight, but in making patients healthier and improving their quality of life. So losing a little bit of weight (e.g. 5% weigh loss) can make you healthier and improve your quality of life and is achievable in many patients without drug treatment.

Obesity is a chronic disease so obesity therapy is a chronic life-long process. If you have a treatment that is effective, it won’t work if you stop the treatment. And that includes both behavior and drug therapy. If you stop the therapy it is likely that you will regain the weight that you lost.