Weight loss can prevent, delay, or reverse type 2 diabetes, but it can be very hard to achieve and maintain. That’s why the approval of semaglutide to treat obesity is causing such excitement.
The diabetes medication semaglutide was recently approved to treat obesity, and other potentially effective obesity medications are in the pipeline. Susan Z. Yanovski, MD, discusses the critical need for effective ways to treat and manage weight for people with diabetes. She also describes semaglutide and other new medications that could make weight loss more feasible for more people with type 2 diabetes—if barriers to their use can be overcome.
Q: How are overweight and obesity linked to type 2 diabetes?
A: Overweight and obesity are strong risk factors for type 2 diabetes. About 80% of adults with type 2 diabetes also have overweight or obesity. Greater levels of obesity confer higher risk for the disease.
In type 2 diabetes, both insulin resistance and reduced pancreatic beta cell function lead to elevated blood glucose. Insulin resistance is very common in people with obesity, who frequently develop impaired glucose tolerance and prediabetes before the diabetes develops—sometimes years beforehand. In fact, almost 35% of U.S. adults have prediabetes. Eventually their beta cells can’t keep up with the increased demand to maintain healthy blood glucose levels in the target range, and they develop diabetes.
Q: Can weight loss prevent or delay the onset of type 2 diabetes?
A: Yes. Even a relatively modest amount of weight loss can prevent or delay diabetes. We know this from the National Diabetes Prevention Program. We also know from studies that the use of anti-obesity medications can also reduce the risk of prediabetes progressing to diabetes. With larger amounts of weight loss, for example from bariatric surgery, remission of type 2 diabetes can occur with a return to healthy blood glucose levels in some patients.
Q: What is the history of medications to manage weight?
A: Unfortunately, anti-obesity medications have had a history of safety problems, which led to several medications being withdrawn from the market. In addition, the amount of weight loss with anti-obesity medications that were approved prior to 2021 has been modest, ranging from an additional 3 to 9 percent loss of initial weight compared with placebo. That’s less than most patients and clinicians would consider acceptable. The greater the weight loss, the greater the reduction in most obesity-related comorbid conditions.
According to the Government Accountability Office, only about 660,000 of more than 70 million Americans with obesity used prescription weight-loss medications from 2012 through 2016. And only about 3% of U.S. adults who are trying to lose weight reported taking those medications between 2013 and 2016.
Q: Semaglutide was approved for weight management by the FDA in June 2021; it had previously been approved as a diabetes medication. What is this medication?
A: Semaglutide belongs to the glucagon-like peptide (GLP-1) receptor agonist class of medications. These are incretin hormones that improve glycemic control by stimulating insulin secretion in response to food intake and hyperglycemia. This lowers both post-meal and fasting blood glucose. Semaglutide is one of several GLP-1 receptor agonists approved to treat diabetes, as second-line agents after metformin.
At the dosage approved for diabetes, GLP-1 receptor agonists not only lower blood glucose, but also reduce weight by about 3-5% of initial weight. Scientists believe this occurs because the medications reduce appetite and they slow down gastric emptying, which can increase a sense of fullness and decrease hunger. In addition, semaglutide and another medication in this class, liraglutide, reduce risk of major adverse cardiovascular events with diabetes.
The weight-loss results in patients prescribed GLP-1 receptor agonists to treat diabetes inspired research to see whether higher dosages would produce even more weight loss. Following this research, liraglutide was approved in 2014 and semaglutide in 2021 to treat obesity, both at higher dosage than that used to treat diabetes. Liraglutide is administered as a daily subcutaneous injection, while semaglutide is injected once weekly.
Q: Why is the health care community particularly excited about semaglutide?
A: The excitement about semaglutide is due to its efficacy for weight loss in people with obesity. At the full dosage of 2.4 milligrams, you see an average weight loss of about 15% of initial body weight, compared to most obesity drugs where you find a 5-10% weight loss. The other reason for excitement is because of the percentage of people who lost really large amounts of weight, with about a third of people losing at least 20% of their initial weight, an amount approaching that seen with some types of bariatric surgery.
These findings came out of the STEP research trials; STEP stands for Semaglutide Treatment Effect in People with Obesity. In the research trials, people with diabetes who received semaglutide with behavioral treatment had somewhat less weight loss than people without diabetes. However, they did lose an average of almost 10% of their initial weight after one year on the medication, which was about 6% more than those who received a placebo.
The STEP trials also looked at what happens when people continue with or discontinue semaglutide after 1 year. They found that when people were switched to a placebo, they regained much of their lost weight, whereas those who stayed on semaglutide continued to lose weight and stabilized their weight loss at about 15% of their initial weight. Results from a follow-up study of semaglutide versus placebo showed that this weight loss can be sustained for at least two years. This reinforces the idea that you really need to treat obesity as you would any other chronic disease.
Q: What do health care professionals need to consider when prescribing semaglutide as a medication to manage weight for patients with diabetes?
A: Clinicians need to consider the patient’s other medications and medical conditions. For example, they shouldn’t be prescribing semaglutide if the patient is taking another GLP-1 receptor agonist or a dipeptidyl peptidase 4 (DPP-4) inhibitor. The patient also shouldn’t use any GLP-1 receptor agonist if they have a personal or family medical history of medullary thyroid cancer or recurrent pancreatitis. Any of the contraindications for GLP-1 receptor agonists when prescribing to treat diabetes will apply when prescribing to treat obesity.
Also, if the patient is on another anti-diabetes medication that can cause hypoglycemia, such as insulin or a sulfonylurea, they will need to be carefully monitored. It’s likely that the dose will need to be adjusted when adding semaglutide, to reduce the risk of hypoglycemia.
Q: What is the cost of semaglutide, and will this be a barrier to uptake?
A: Cost is a major concern for use of all prescription medications to treat overweight and obesity. They’re often excluded from reimbursement by insurers, including Medicare, some state Medicaid programs, and many private insurers. Most people taking anti-obesity medications pay for them out of pocket, and they can be very expensive.
That’s why the most prescribed obesity medication is phentermine, which is a generic medication that’s only approved for short-term use and has not been tested in long-term studies. A medication like semaglutide, with the cost of about $1,300 a month, is going to be prohibitive for many patients who could benefit. Cost may also even be a barrier for patients with insurance that covers the medication, because of copays.
However, reimbursement is better for semaglutide when prescribed at the lower dose levels to treat diabetes. We’re fortunate that we now have medications in two classes, sodium-glucose co-transporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists, that have been shown to reduce major adverse cardiovascular events and have a favorable impact on weight when used by patients with type 2 diabetes. When clinicians are adding medications to metformin to improve glycemic control in patients with overweight or obesity and type 2 diabetes, they may want to consider either an SGLT2 inhibitor or a GLP-1 receptor agonist.
Q: What other weight-loss medications are in the research pipeline?
A: It’s an exciting time for the development of new obesity treatments. Just this past year, setmelanotide was approved for adults and children with some rare forms of genetic obesity. This drug isn’t appropriate for most people because obesity usually has multiple causes, not just alterations in single genes. However, it demonstrates the promise of targeting anti-obesity therapy to specific underlying mechanisms, which is a step towards precision obesity treatment.
There are also new incretin medications being developed that target more than one receptor, both to treat diabetes and obesity, including one called tirzepatide. The results of Phase 3 studies were presented at the American Diabetes Association meeting in summer 2021, and it showed very high efficacy for both glycemic control and weight loss. We’re still waiting for more data from studies of these other medications; they are not yet approved for diabetes or obesity treatment.
Watch the JAMA Network video featuring Dr. Yanovski, Pharmacotherapy for Obesity.
How do you discuss medications to manage weight with your patients with diabetes?