As a cardiologist, I deal with conditions that lead to heart disease, including high blood pressure, high blood cholesterol, diabetes and obesity. As any doctor will tell you, the hardest of these to treat is obesity.
Of course, the usual approach is to go on a diet, but in reality, weight-loss diets don’t work very well. Researchers define a successful diet as one that produces a weight loss of 5 percent. In other words, it’s a success if a 250-pound man loses 12 pounds. Probably, what he would really like is to weigh what he did when he graduated from high school—185 pounds, maybe. He would undoubtedly look and feel better. He would also reduce his risk of diabetes, high blood pressure, heart disease and arthritis of his knees, hips and back. Unfortunately, that kind of weight loss from dieting is rare.
Now there’s a more effective way to lose weight. In 1990, Dr. John Eng, an endocrinologist at the Veterans Administration Center in the Bronx, N.Y., discovered that the saliva of an American lizard know as a Gila Monster contains a hormone that’s almost identical to the human hormone GLP-1 (Glucagon-Like Polypeptide). Scientists had discovered that human GLP-1 lowers blood sugar, suggesting that it might be useful as a medicine for diabetes.
Although chemists could synthesize human GLP-1, it didn’t last long enough in the circulation to be useful a medication. However, Dr. Eng found that Gila Monsters’ GLP-1 lasted longer than human GLP, which made it possible to use as a medication. In 2005, the pharmaceutical company Eli Lilly began marketing a synthetic version of Gila monster GLP-1 under the brand name Byetta for treating diabetes. Doctors jokingly called it lizard spit.
Research trials showed that in addition to lowering blood sugar, exenatide caused some weight loss, an average of 2% of initial body weight. That might not sound like much, but it was notable because most of the diabetes medications at the time made patients gain weight.
The amount of fat you carry is controlled by the balance among several hormones, some of which promote fat accumulation, some of which promote fat loss. GLP-1 is a hormone secreted by your intestine that helps you shed excess fat. GLP-1 medications are replicas of natural GLP-1 modified to stay in your system longer.
Although exenatide lasted longer in the circulation than human GLP-1, it still disappeared quickly requiring an injection twice a day. Biochemists went to work to develop longer lasting versions of GLP-1. Now there are several GLP-1 medications that stay in the circulation longer than exenatide and are easier to take. For example, liraglutide (brand name Victoza) can be taken once daily. Semaglutide (brand names Ozempic and Wegovy) and terzepatide (brand name Mounjaro) require only one self-administered injection per week.
While all the GLP-1 medications are effective for controlling blood sugar, they differ in the amount of weight loss they produce. In diabetics, Victoza causes an average loss of 6 percent of initial body weight; Ozempic produces a loss of 7 percent. Remember, that’s in diabetics.
This brought up the obvious question: If GLP-1 medications help diabetics lose weight, why couldn’t they be used to help folks without diabetes shed pounds? To answer that question, researchers enrolled 1961 overweight volunteers without diabetes to see if the long-lasting GLP-1 medication Ozempic could help them lose weight. Two thirds of the participants gave themselves an injection of Ozempic once a week. One third took a placebo shot.
The results were astonishing. In a year and 4 months, the participants who took Ozempic lost 16 percent of their body weight–an average of 34 pounds. Unlike most diets, after which more than half the pounds lost in the first 6 months usually return in a couple years, the weight loss from Ozempic remained until the study ended two years later.
If those results weren’t impressive enough, in 2022 the findings of a study of another GLP-1 diabetes drug, terzepatide (Mounjaro), were published. One weekly shot of Mounjaro produced an average weight loss of 48 pounds–21 percent of initial weight. You read that right: one self-administered shot a week, 48 pounds. No treatment for obesity has ever come close to producing that much weight loss.
This is a game changer. A cure for obesity could reverse or prevent all the medical problems caused by being overweight, including type 2 diabetes, high blood pressure, heart disease and arthritis of the knees and hips. For many people, it would open the door to a world of leisure and work activities and alleviate the embarrassment and self-esteem issues associated with obesity.
The day might come when treating obesity would be like treating high blood pressure. The goal of treatment of high blood pressure is not just to lower it a few points but to get it to a “target” — a pressure that’s low enough to prevent damage to your blood vessels. Similarly, if you have high cholesterol, the goal of treatment is to lower it to a target level where it won’t build up in your arteries. Maybe the time will come when you could treat obesity the same way– choose a desirable weight and keep shedding pounds until you get there.
Ozempic comes in prefilled pens. There is no need to draw medicine out of a vial. The needles are smaller and thinner than ones used, for example, for flu shots. The injection is virtually painless.
GLP-1 is a protein, and like the protein in food, if you took it orally your digestive system would break it down to smaller molecules, which would cause it to lose its effectiveness. This is why most GLP-1 medications must be taken by injection. One exception is Rybelsus, a form of Ozempic that is encased in a special capsule that allows it to be absorbed directly into the bloodstream through the lining of your stomach, thereby avoiding digestion in the intestine. At least in diabetics, Rybelsus taken daily causes almost as much weight loss as weekly Ozempic injections do, although it hasn’t been tested in a controlled research trial in people without diabetes.
Rybelsus appeals to folks who are hesitant about giving themselves shots. Because of the unique way in which Rybelsus is absorbed into the bloodstream–through the lining of the stomach rather than the intestine–it must be taken on an empty stomach, and food and beverage must be avoided for 30 minutes afterwards.
GLP-1 medications have been used since 2005 to treat diabetes and have been remarkably free of serious side-effects. You might wonder why these drugs weren’t used earlier to help people without diabetes lose weight. The FDA is especially careful when it comes to approving drugs for weight loss. They knew that if GLP-1 medications really worked for losing weight, a lot of people would want to take them. The FDA considered it particularly important to be sure the medications were safe and effective before allowing them to be prescribed to people who don’t need them for diabetes.
Questions That Remain
It’s only been a few years that GLP-1 medications have used for treating obesity, so longer-range results are unknown. As long as the medication is continued, the weight stays off for at least a couple of years. The question remains whether weight loss is permanent if you keep taking the drug. It’s also unknown whether weight loss can be maintained after stopping the medication.
Among folks who lose weight by dieting, those who are successful at keeping the weight off have one thing in common: they take advantage of being lighter on their feet and more agile to commit themselves to a meaningful exercise routine. Whether the same would apply after stopping GLP-1 medication is unknown.
The most common side-effects of taking GLP-1 are nausea and diarrhea. These can usually be avoided if treatment is started with low doses that are slowly increased. If nausea or diarrhea does occur, it can usually be resolved by temporarily reducing the dose. Studies show that weight loss from GLP-1 medications is not dependent upon them causing nausea.
Serious long term side effects from GLP-1 medications are rare. Indeed, trials show that diabetics who take them on average have fewer heart attacks and live longer than those who don’t. Ultra-high doses produce tumors in laboratory animals, but this is true of many drugs. GLP-1 medications have been used for two decades to treat diabetes in humans and have not been shown to cause tumors.
