GLP-1 Agonists for Diabetes, Obesity, and Heart Health

Every day there seems to be a new headline about GLP-1 agonist drugs.^1-4

These medications, which include Ozempic® and Wegovy®, were first used to help control blood glucose levels in patients with type II diabetes.^5-8

Clinical trials confirmed blood sugar benefits and showed that these medications also reduce risk of cardiovascular events in diabetics, including heart attack and stroke, by as much as 26%.^9-11

Like any medication, GLP-1 agonists come with potential downsides.^12-16 Consult your doctor if you believe you may be a candidate for one of these drugs.

What are GLP-1 Agonists?

GLP-1 agonists are a relatively new class of drugs. They bind to and activate a cellular receptor for the hormone GLP-1 (glucagon-like peptide-1).

This cell receptor is most abundant in the insulin-secreting part of the pancreas. It is also present in the nervous system, and throughout the gastrointestinal tract, as well as the cardiovascular system, kidneys, and lungs.^17,18

The formal name of this drug class is GLP-1 receptor agonists, but in common usage this has been shortened to GLP-1 agonist.  These drugs act on the GLP-1 hormone receptor.

First developed as anti-diabetes medications, in the pancreas these drugs stimulate production of insulin, the hormone that helps reduce blood glucose levels after a meal.^3,19

They also slow down the emptying of the stomach after eating and promote a feeling of fullness or satiety.¹⁹

Multiple meta-analyses of randomized controlled clinical trials have firmly established that GLP-1 agonist drugs are highly effective in type II diabetics for reducing blood sugar as well as hemoglobin A1C, a marker of longer-term glucose control. Some of these studies also found that these medications reduce systolic blood pressure.^5,6,8

What has received so much attention is that these and other studies have also found that patients taking this class of drugs have had significant weight loss.

In part, this is because GLP-1 agonists activate receptors in the area of the brain that controls hunger.^3,19,20 They stimulate satiety, the sense of feeling full after a meal, reducing cravings and caloric intake.GLP-1 agonists are approved for use in some people with type II diabetes, and two of them are FDA-approved for weight loss in certain people and situations.

In such individuals starting a GLP-1 agonist drug, it is recommended to also adopt a reduced-calorie meal plan and to increase physical activity at the same time.

Impressive Clinical Results

GLP-1 agonists have been found to offer benefit for a variety of common chronic conditions. Here are a few highlights:

Type II Diabetes

Meta-analyses of placebo-controlled trials of GLP-1 agonists in patients with type II diabetes^5,6,8 have consistently shown that they are effective at reducing blood glucose.^5-8

A hemoglobin A1c (HbA1c) test shows the average blood sugar level over two to three months. This value is higher in those with poor glucose control. In many clinical studies, use of a GLP-1 agonist has resulted in significantly lower HbA1c levels.

Weight Loss

The meta-analyses of randomized controlled trials in type II diabetics referenced above also found that, on average, subjects lost significant weight while taking these medications.^5,6,8

In a trial of non-diabetic adults with obesity,²¹ all patients received a lifestyle intervention and were randomized to receive either weekly injections of semaglutide—the drug in Ozempic® and Wegovy® — or placebo. The semaglutide group experienced an average of nearly 15% reduction in body weight after 68 weeks, compared to 2.4% in a placebo group.

This corresponds to an average loss of almost 34 pounds in the treatment group, compared to less than six pounds in those who took a placebo.

Reduction in Cardiovascular Events

Both diabetes and obesity are risk factors for cardiovascular disease, which is damaging to both the heart and blood vessels. Rates of cardiovascular disease are much higher in those with poorly controlled diabetes and/or excess body weight. It makes sense that by controlling blood glucose and reducing weight, GLP-1 agonists could also lower cardiovascular risk.

Recent analyses have started to look at these effects and here too the results are encouraging. A meta-analysis of randomized controlled trials that included over 56,000 subjects taking GLP-1 agonists for diabetes found that the drugs reduced major cardiovascular events (including stroke and heart attack) and death from cardiovascular and all causes by 12%.¹⁰

Two trials ^9,11 designed specifically to test cardiovascular effects of these drugs found that type II diabetics treated with semaglutide had a remarkable 21% and 26% reduction in risk for major cardiovascular events, including non-fatal stroke and heart attack, and death from cardiovascular causes.

To evaluate whether GLP-1 agonists could improve cardiovascular health in people without diabetes, the recent SELECT trial enrolled 17,604 nondiabetics overweight or obese adults with cardiovascular disease.²² They were randomized to receive semaglutide or a placebo.

The results of this trial have not been published in the medical literature yet, so they should be assessed with caution. But the preliminary results reported in the news and on the drug company's website.^1,23 have exceeded expectations. Even in those without diabetes, use of this drug led to a 20% reduction in cardiovascular events and death.

These findings show that GLP-1 agonists can be game changers in improving blood glucose control and body weight and in reducing risk of cardiovascular events and death.

What You Need to Know

The Skinny About GLP-1 Agonists

• Drugs called GLP-1 agonists, which include Ozempic® and Wegovy®, have caused a buzz in the medical community and the media.
• Originally designed to reduce blood glucose levels in people with type II diabetes, GLP-1 agonists also promote significant weight loss in obese or overweight adults.
• Clinical trials have also found that GLP-1 agonists can reduce risk for major cardiovascular events, including cardiovascular-related death, heart attack, and stroke, by 20% or more.
• Gastrointestinal problems are common side effects, and safety concerns remain about long-term use. Consult a doctor if you think GLP-1 agonists may benefit you.

Need for Caution

GLP-1 agonists have been generally well tolerated in trials. However, there are potential concerns that should be considered before starting these medications.^4,14,16,24

Gastrointestinal side effects, including nausea and vomiting at higher doses, are by far most common,²⁵ and a reason for discontinuation of treatment.^25,26 Therefore, starting with lower doses and a slower dose titration may help minimize this risk.²⁷

For those patients using GLP-1 agonist drugs for weight loss, various side effects have been reported including nausea, vomiting, abdominal pain, diarrhea, constipation, gastroenteritis, and certain incidents of pancreatitis and bowel obstruction.^28-31

Anyone considering using a GLP-1 agonist should consult with a doctor and weigh potential side effects against the many benefits.

Summary

GLP-1 agonists are the subject of tremendous "buzz" and exuberance in the medical community and the media.

Originally designed to help manage type II diabetes, these medications have also been found to induce significant weight loss.

Clinical trials show that these drugs also reduce cardiovascular events and death by 20% or more in those with type II diabetes and in overweight or obese adults without diabetes.

GLP-1 agonists can cause gastrointestinal symptoms, and concerns remain about their long-term effects, but they have tremendous potential to control blood sugar, promote weight loss, and protect cardiovascular health.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

1. Available at: https://www.cnn.com/2023/08/08/health/wegovy-heart-trial/index.html. Accessed Feburary 13, 2024.
2. Available at: https://news.harvard.edu/gazette/story/2023/07/are-new-weight-loss-drugs-the-answer-to-americas-obesity-problem/. Accessed Feburary 13, 2024.
3. Available at: https://www.keckmedicine.org/blog/ozempic-for-weight-loss-los-angeles/. Accessed August 15, 2023.
4. Available at: https://www.uchealth.org/today/wegovy-vs-ozempic-the-truth-about-new-weight-loss-drugs/. Accessed August 15, 2024.
5. Andreadis P, Karagiannis T, Malandris K, et al. Semaglutide for type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Obes Metab. 2018 Sep;20(9):2255-63.
6. Avgerinos I, Michailidis T, Liakos A, et al. Oral semaglutide for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. 2020 Mar;22(3):335-45.
7. Holmes P, Bell HE, Bozkurt K, et al. Real-World Use of Once-Weekly Semaglutide in Type 2 Diabetes: Results from the SURE UK Multicentre, Prospective, Observational Study. Diabetes Ther. 2021 Nov;12(11):2891-905.
8. Li A, Su X, Hu S, Wang Y. Efficacy and safety of oral semaglutide in type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2023 Apr;198:110605.
9. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-51.
10. Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-85.
11. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-44.
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21. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021Mar 18;384(11):989-1002.
22. Lingvay I, Brown-Frandsen K, Colhoun HM, et al. Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics. Obesity (Silver Spring). 2023 Jan;31(1):111-22.
23. Available at: https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=166301. Accessed August 15, 2023.
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26. Available at: https://news.northwestern.edu/stories/2023/12/nearly-40-of-type-2-diabetes-patients-stop-taking-their-second-line-medication/#:~:text=The%20scientists%20analyzed%20five%20non,%E2%80%9CDiscontinuation%20is%20bad. Accessed Feburary 16, 2024.
27. Available at: https://illinoisadvance.com/what-are-gastrointestinal-adverse-effects-glucagon-peptide-1-receptor-agonists-and-how-should-they-be-managed/. Accessed Feburary 16, 2024.
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31. Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023;330(18):1795-7.