This article was written in collaboration with Dr. Timothy Garvey, MD.
Professor; Director, Diabetes Research Center
TREATMENT FOR OVERWEIGHT AND OBESITY
The prevalence of obesity, defined by excess body fat causing compromise to health, has increased over the last few decades. It is estimated that up to 49% of the world’s population and 70% of the US population are overweight or obese. Rates of overweight, defined as body mass index (BMI) >25, and obesity (BMI >30) have increased over the last decade. By 2030, one in two US adults will have obesity, and one in four will have severe obesity (BMI >40), with even higher rates among certain socio-demographic subgroups.
What is the definition of Obesity?
Obesity can be defined as BMI or Body Mass Index, which is a measure of body fat based on height and weight that applies to adult men and women, and its impact on health and weight-related complications. These complications can be metabolic and involve the accumulation of visceral fat with increased abdominal or waist circumference (>40 inches in men and >35 inches in women), abnormal lipids (elevated Triglyceride (>150 mg/dL), and low HDL cholesterol (<40 mg/dL in men and <50 mg/dL in women), hypertension defined as >130/80, pre-diabetes with HbA1C >5.7%, non-alcoholic liver fatty infiltration, or fat around the heart (pericardial fat). Other complications can be biomechanical and involve the presence of sleep apnea, osteoarthritis, GERD, urinary incontinence, and depression.
Overweight is classified by BMI between 25 and 30 (kg/m2), Obesity with BMI >30, and severe obesity with BMI >40.
What is the relationship between Obesity and Diabetes Mellitus?
Some patients can be obese but still metabolically healthy. This depends on their genetically predetermined insulin sensitivity. Over time, however, a large number of these patients will develop unhealthy obesity with complications such as diabetes. The accumulation of visceral fat is an abnormal fat and is insulin resistant. Patients should be followed prospectively for the development of complications and encouraged to decrease their caloric intake, particularly in refined sugars, and remain physically active.
What are the tools to combat Obesity?
- Healthy Lifestyle:
Expert panels recommend that obese adults, as well as adults with overweight and comorbid conditions, lose 10% of their initial body weight. A comprehensive program of life modification is considered the first step to achieving this goal. Comprehensive lifestyle modification programs provide sessions to modify eating and activity habits. Obese individuals can lose weight by following reducing diets that vary widely in macronutrient composition whether it is low carb or low fat. A diet following the Mediterranean diet concept allows for cardiometabolic protection. Caloric restriction is the key determinant of weight loss. The choice of a diet should also address patient preferences since it will facilitate adherence.
Physical activity plays a critical role in improving cardiovascular health in average-weight and obese individuals. Even in the absence of significant weight loss, aerobic physical activity has been shown to reduce blood pressure, lipids, and visceral fat which is related to improved glucose tolerance and insulin sensitivity, and glycemic control in diabetic patients. Physical exercise can facilitate the maintenance of lost weight. The most recent WHO guidelines on physical activity recommend that adults perform at least 150-300 mins of moderate-intensity aerobic exercise (65% to 75% max heart rate), a 75-150 mins of vigorous-intensity (76% to 93% max heart rate) aerobic exercise or an equivalent combination of the two, each week. Muscle strengthening exercises involving all major muscle groups should also be performed 2d/wk at a moderate intensity. Adherence to these guidelines is associated with a 23% to 40% reduction in cardiovascular mortality and a 30% reduction in all-cause mortality.
- Bariatric treatment of Obesity:
Surgical treatment of Obesity constitutes the gold standard of Obesity treatment. It is recommended for patients with severe obesity with a BMI of >40, patients with BMI>35 and one or more severe obesity-related comorbidities, and patients with a BMI of 30-35 with uncontrolled diabetes mellitus or metabolic syndrome.
Different types of surgeries are available. However, the adjustable gastric band is not recommended any more due to complications and relatively minimal weight loss achieved compared to other techniques. The laparoscopic gastric sleeve resects most of the body and all the fundus of the stomach creating a long narrow tubular stomach. It has gained popularity in recent years. It produces on average a weight loss of 15-28%. In the Roux-en-Y gastric bypass, a small pouch is formed by dividing the upper stomach and joining it to the resected part of the jejunum, excluding the duodenum. The food bypasses the stomach and the upper small bowel thereby restricting the size of the stomach and causing some malabsorption. This may be a better choice in patients with severe obesity and uncontrolled diabetes mellitus.
Gastric bypass reduces the weight by an average of 25-35% and reduces the risks of cardiovascular disease; including myocardial infarction, congestive heart failure, and strokes and improves mortality in patients with severe obesity.
- Medical treatment of Obesity:
The medical therapy for obesity has had a difficult start with poor safety and efficacy track- records of previous anti-obesity drugs and the lack of compelling targets for drug discovery.
Effective medical management requires first and above all a multi-prong approach to lifestyle which must be maintained during the follow-up. Pharmacotherapy is not a cure for obesity because of the complex interaction between social and physiological factors that cause and sustain obesity. Safety has been the downfall of many drugs in the past with fenfluramine that were withdrawn because of evidence of small but definite incidence of pulmonary hypertension and valvular heart disease.
The use of dietary supplements is very common among people trying to lose weight. Some common therapies include caffeine, chromium, cinnamon, garcinia, and green tea extract. The FDA does not regulate the supplement industry, but after several reports of harm associated with the use of weight loss products, the FDA has withdrawn many weight loss ingredients of non-prescription products including ephedra, phenylpropanolamine, aloe, cascara sagrada. There is a lack of scientific evidence for most dietary supplements which achieve very minor weight loss benefits and have significant side effects and interactions with other medications.
Phentermine is a sympathomimetic that works at the level of the melanocortin/cocaine and amphetamine-regulated transcript of the arcuate nucleus of the brain and was initially approved in 1959 for the treatment of obesity. It is currently used in combination with Topiramate, an anticonvulsant medication that modulates the GABA receptors of the higher cortical centers to decrease appetite. In clinical trials compared to placebo, the combination of Phentermine/Topiramate achieved an average weight loss of 9% from baseline, at 1 and 2 years in the Sequel clinical study.
Naltrexone acts on the arcuate nucleus of the brain and when combined with Bupropion, which acts on the dopamine/Neurotransmitters reuptake of the cortical centers of the brain to suppress appetite, results in an average 4-5% weight loss from baseline of the studies.
Orlistat is a synthetic drug that blocks the digestion and absorption of approximately 30% of dietary fat and accounts for part of its weight-reducing effect. In the Xendos study, Orlistat (Xenical) produced an average weight loss of 4%.
Liraglutide is a Glucagon-like peptide-1 (GLP-1) receptor agonist that in addition to stimulating insulin release and reducing glucagon secretion, slows gastric emptying and increases satiety after eating. It was approved for the treatment of obesity in 2014 under the name of Saxenda. In the Scale maintenance study, liraglutide was administered at a dose of 3 mg sc daily for 1 year in overweight and obese patients who did not have diabetes. The average weight loss compared to placebo was 6% with two third losing 5% and one-third losing >10%. The main side effect was nausea and diarrhea.
The Second Generation Obesity Medications should be able to produce a mean weight loss of >10% and a >15% weight loss in over half of patients in conjunction with lifestyle intervention.
Semaglutide is a newer GLP-1 receptor agonist and was approved for the treatment of obesity in June 2021. In the STEP clinical study, adults with BMI>30 or >27 with the presence of weight-related condition but who did not have diabetes, were treated with Semaglutide 2.4 mg once weekly sc injection for over 1 year in addition to a healthy lifestyle. The treated group had a mean change of 14.9% body weight loss vs 2.4% for control with lifestyle only. The 2 year efficacy of Semaglutide 2.4 mg in the STEP 5 trial produced >5% weight loss in 83%, >10% in 67%, >15% in 56% and >20% in 39%.
Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GLP-1/GIP agonist) that was just approved in May 2022 for the treatment of type 2 diabetes. In the SURMOUNT study, adults with BMI >30 or >27 with obesity-related conditions and without diabetes, received once-weekly sc injections of 5, 10, and 15 mg or placebo for 72 weeks, including a 20-week escalation dose period. The mean % change in body weight was 15% with the 5 mg dose, 19.5% with the 10 mg dose, and 20.9% with the 15 mg dose in addition to lifestyle modifications vs 3% with placebo. Overall, 50% of participants in the 10-15 mg group had a reduction of weight loss of 20% or more with improvement in all cardiometabolic measures. The most common side effects were mild to moderate gastrointestinal symptoms that were experienced during the escalation dose causing a discontinuation rate of 4-6% vs 2% in the placebo group.
Because of the advances in the treatment of obesity, the paradigm shift has been to use the % of weight loss as a biomarker that can be actively managed with optimal outcomes in patients with obesity like HbA1c in diabetes, blood pressure readings in hypertension, LDL levels in hyperlipidemia. Different complications require different amounts of weight loss for prevention and treatment of complications. In patients with prediabetes, a 10% weight loss is effective in preventing diabetes mellitus. In patients with diabetes, the more weight loss, the better: 5-15% of weight loss provides a reduction in HbA1c, blood pressure, and abnormal lipids.
Sleep apnea is improved with weight loss of >10% and fatty liver with 5-10% of weight loss. In the AHEAD study, a >10% of weight loss reduced the primary outcome of CVD death, myocardial infarction, stroke, or angina hospitalization by 21%. The SELECT study of Semaglutide 2.4 mg sc weekly vs placebo in nondiabetic patients with Obesity started enrolling patients >45 yrs with BMI >27 kg/m2 with established CVD (prior MI, prior CVA, or symptomatic PVD) in 2018 and will complete enrollment in 2023. Overall, 17,500 patients will be included and monitored for CV death, non-fatal MI, and non-fatal stroke