Wegovy, Ozempic, Tirzepatide: The Pros and Cons

Authors: Joshua Engle, MD; Kimberly Jacobson RDN

Disclaimer of Financial Interest:

I am the founder and Chief Medical Officer of ExciteMD. At ExciteMD, we pair medically assisted weight loss with a nutritionist-led diet and exercise plan to help clinically obese patients lose weight. My goal in this article is to write a balanced perspective on weight loss pharmaceutical tools, not to blindly promote them.

Introduction: Unless you have been living under a rock, you have most likely heard about Wegovy and Ozempic. A lot of people are using these medications for weight loss. You are probably wondering if these medications work. You are also probably wondering about any potential side effects of these medications. Here we will explore both, as well as who should be on these medications, and more importantly, who shouldn’t.

What is Ozempic/Wegovy/Tirzepatide and How It Works: The active ingredient in these medications is Semaglutide. Semaglutide was originally developed and used to treat diabetes. Semaglutide is what is called a GLP-1 agonist. That means it works by copying a natural hormone in our body called GLP-1, making us feel full faster when we eat [1]. So, when someone takes Semaglutide (Wegovy or Ozempic), they will likely eat less because of this effect. This can help people lose weight over time.

Tirzepatide, in addition to having the GLP-1 component, also has a molecule called glucose-dependent insulinotropic polypeptide, or GIP for short. GIP helps control your glucose levels, aka the amount of sugar in your blood [2]. This in turn can work synergistically with the GLP-1 agonist to help with your weight loss.

The Evidence Supporting The Use of These Agents For Weight Loss: There are two landmark trials investigating Semaglutide for weight loss: The Step 1 trial and the Sustain 8 trial.

For the Step 1 trial, from June through November 2018, a total of 1961 participants were randomly assigned to receive Semaglutide (1306 participants) or placebo (655 participants). The primary endpoints were the percentage change in body weight from baseline to week 68 and the achievement of a reduction in body weight of 5% or more from baseline to week 68. Body composition (total fat, total lean body mass, and regional [abdominal] visceral fat mass) was measured via a DEXA[1] scan in a subpopulation of 140 participants in the study. The mean change in body weight from baseline to week 68 was ?14.9% in the Semaglutide group compared with ?2.4% with placebo. More participants in the Semaglutide group than in the placebo group achieved weight reductions of 5%, 10%, and/or 15% or more [3].

For the Sustain 8 trial, 788 patients were randomly assigned to either Semaglutide or Canagliflozin (another type of diabetes medication). Semaglutide led to an increased reduction in body weight versus Canagliflozin (-5.3 kg versus -4.2 kg) [4].

Overall, with these agents, the decrease in appetite and craving for fatty/energy‐rich foods, and better control of eating are the most likely mechanisms for Semaglutide-induced weight loss [5].

Potential Draw Backs When Using These Agents:

Risk of Lean Mass Loss: While there is no doubt that these agents help with total weight loss, there is evidence that not all the weight loss when using these agents comes from fat. In sub-analyses in both the above studies, 40% of weight loss came from lean muscle mass [6, 7]. Some degree of mean muscle mass loss when losing weight is unavoidable. Researchers have found lean muscle mass, on average, comprises 25% of total weight loss [8, 9]. However, per the 40% lean muscle mass loss observed in the two landmark trials outlined above, it would appear that lean muscle weight loss from Wegovy/Ozempic is in excess of the weight loss that comes from lifestyle/exercise alone.??

Weight Regain After Stopping Semaglutide: One year after the withdrawal of once‐weekly subcutaneous Semaglutide 2.4 mg, participants regained two‐thirds of their prior weight loss, with similar changes in cardiometabolic variables. These findings may suggest ongoing treatment is required to maintain improvements in weight and health [10].

Nausea, Constipation and Other Gastrointestinal Side-Effects: The most common side effect of these weight loss agents are gastrointestinal symptoms (nausea, constipation, and/or diarrhea) [11]. One of the ways these agents help people lose weight is by slowing down the movement of food through their GI tract (stomach and intestines). If your GI tract is moving slower, that means what is left of the food (stool) is going to reach your bottom slower. Hence complaints of constipation. Also, if food is moving through your GI tract more slowly, that means things move out of your stomach more slowly. By itself this isn’t a problem. But if you eat while a significant amount of food is still in your stomach, that can lead to nausea.?

Do The Above Drawbacks Mean These Agents Shouldn’t Be Used For Weight Loss: In a word: No. Obesity leads to a 20% increase in all-cause mortality [12]. Obesity significantly increases adverse cardiovascular events such as heart attacks [13]. Obesity puts an increased weight load on your back and knees leading to osteoarthritis [14], which in turn leads to pain and degradation in these areas. Adipose is pro-inflammatory [15], which can lead to its own health complications, including an increased risk of certain cancers [16]. For COVID patients, obesity is a huge risk factor for adverse outcomes. Not to mention, overall, you will just feel more crummy and less energetic if you are obese.

Also, there is more nuance to GLP-1 agonists causing lean muscle mass loss. I will spare you from going down the rabbit hole, but briefly there is evidence that obese people have increased fat in their actual muscle tissue [17]. Therefore it is unclear if, of the lean muscle mass loss in GLP1 patients, what percent of that lean muscle mass is truly from lean muscle, and not just fat in the muscle.

The above points don’t mean we should ignore the drawbacks mentioned earlier in this article. So the best strategy is not to completely avoid GLP-1 agonists, but to mitigate the drawbacks associated with them. So this is how we do that:

·????? Only work with clinically obese patients with a BMI[2] greater than 30. So folks who are just a tad overweight and want to look good at the beach, I would not recommend GLP-1 agonists. All healthy weight loss should be encouraged. But you would be better served with just lifestyle interventions alone.

·????? Do resistance training to prevent muscle mass loss. Even during weight loss, this has been found to significantly limit the amount of weight loss from lean muscle. [18, 19].

·????? High protein intake can also prevent lean muscle mass loss. The recommended dietary allowance is 0.8 grams per kilogram (not pounds) of body weight [20]. However, evidence suggests that 1-2 grams per kilogram may actually be optimal, especially when losing weight [20].

·????? Use Clinically Validated scales to make sure you are staying on the right side of your lean muscle mass to total weight ratio as you are losing weight. I bolded the clinically validated part because a lot of scales claim to be clinically validated, or worse yet, just make vague claims of being “trusted” or “accurate”. It actually took us a really long time to find the scales we work with. Any scales you use should publicly release their peer-reviewed data/studies.

·????? Not everyone needs the highest dose of GLP-1 agonist. For example, the usual protocol is titrating Ozempic up to 2mg [21]. However, if you are getting great results at a lower dose, I say lets stay there. This will also aid in getting off medication when you choose.

At ExciteMD we are happy to guide you through these nuances. Regardless of whether you choose to work with us, we hope this information helps!

Footnotes:

?[1] A DEXA scan, also known as a bone density scan, is a medical test that uses low-dose X-rays to measure the amount of calcium and other minerals in a section of bone. This helps doctors determine the strength of your bones and assess your risk of fractures. It can also be used to assess both lean (muscle) and fat mass.

[2] BMI = Body Mass Index. It is a measure of height versus weight. BMI has gotten a bad wrap. I will be the first to admit this metric isn’t perfect. Metrics such as body fat percentage, waist-to-hip ratio, and fat around the waist are better indicators of healthy weight and metabolic health. But BMI is still a decent quick and dirty way to get a sense of someone’s weight status. Also, a lot of the failures around BMI come from a specific patient group: males who do high-weight resistance training. In these patients, there is a propensity for high amounts of muscle mass to throw off the BMI measurement. But as clinicians we have eyes. So if someone has a “high” BMI, but looks like a Greek god, I know not heavily weight that metric.

References:

1.???????? Chao AM, Tronieri JS, Amaro A, Wadden TA: Semaglutide for the treatment of obesity. Trends Cardiovasc Med 2023, 33(3):159-166.

2.???????? Min T, Bain SC: The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type?2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther 2021, 12(1):143-157.

3.???????? Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA et al: Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021, 384(11):989-1002.

4.???????? Lingvay I, Catarig AM, Frias JP, Kumar H, Lausvig NL, le Roux CW, Thielke D, Viljoen A, McCrimmon RJ: Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol 2019, 7(11):834-844.

5.???????? Anam M, Maharjan S, Amjad Z, Abaza A, Vasavada AM, Sadhu A, Valencia C, Fatima H, Nwankwo I: Efficacy of Semaglutide in Treating Obesity: A Systematic Review of Randomized Controlled Trials (RCTs). Cureus 2022, 14(12):e32610.

6.???????? John P.H. Wilding DM, Rachel L. Batterham, M.B., B.S., Ph.D., Salvatore Calanna, Ph.D., Melanie Davies, M.D., Luc F. Van Gaal, M.D., Ph.D., Ildiko Lingvay, M.D., M.P.H., M.S.C.S., Barbara M. McGowan, M.D., Ph.D., Julio Rosenstock, M.D., Marie T.D. Tran, M.D., Ph.D., Thomas A. Wadden, Ph.D., Sean Wharton, M.D., Pharm.D., Koutaro Yokote, M.D., Ph.D., et al.: Step 1 Supplementary Appendix. New England Journal of Medicine 2021.

7.???????? McCrimmon RJ, Catarig AM, Frias JP, Lausvig NL, le Roux CW, Thielke D, Lingvay I: Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial. Diabetologia 2020, 63(3):473-485.

8.???????? Heymsfield SB, Gonzalez MC, Shen W, Redman L, Thomas D: Weight loss composition is one-fourth fat-free mass: a critical review and critique of this widely cited rule. Obes Rev 2014, 15(4):310-321.

9.???????? Lean mass loss on GLP-1 receptor agonists: a downside of the “miracle drugs”

10.?????? Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, Lingvay I, McGowan BM, Oral TK, Rosenstock J et al: Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab 2022, 24(8):1553-1564.

11.?????? Semaglutide (Subcutaneous Route) [https://www.mayoclinic.org/drugs-supplements/semaglutide-subcutaneous-route/side-effects/drg-20406730?p=1]

12.?????? Borrell LN, Samuel L: Body mass index categories and mortality risk in US adults: the effect of overweight and obesity on advancing death. Am J Public Health 2014, 104(3):512-519.

13.?????? Powell-Wiley TM, Poirier P, Burke LE, Després JP, Gordon-Larsen P, Lavie CJ, Lear SA, Ndumele CE, Neeland IJ, Sanders P et al: Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation 2021, 143(21):e984-e1010.

14.?????? Reyes C, Leyland KM, Peat G, Cooper C, Arden NK, Prieto-Alhambra D: Association Between Overweight and Obesity and Risk of Clinically Diagnosed Knee, Hip, and Hand Osteoarthritis: A Population-Based Cohort Study. Arthritis Rheumatol 2016, 68(8):1869-1875.

15.?????? Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB: Elevated C-reactive protein levels in overweight and obese adults. Jama 1999, 282(22):2131-2135.

16.?????? Pati S, Irfan W, Jameel A, Ahmed S, Shahid RK: Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management. Cancers (Basel) 2023, 15(2).

17.?????? Cava E, Yeat NC, Mittendorfer B: Preserving Healthy Muscle during Weight Loss. Adv Nutr 2017, 8(3):511-519.

18.?????? McCarthy D, Berg A: Weight Loss Strategies and the Risk of Skeletal Muscle Mass Loss. Nutrients 2021, 13(7).

19.?????? Frimel TN, Sinacore DR, Villareal DT: Exercise attenuates the weight-loss-induced reduction in muscle mass in frail obese older adults. Med Sci Sports Exerc 2008, 40(7):1213-1219.

20.?????? Here’s How Much Protein You Need in a Day to Build Muscle [https://www.healthline.com/health-news/how-much-protein-per-day-build-muscle#How-much-protein-do-I-need?]

21.?????? Dosing for Ozempic? (semaglutide) Injection [https://www.ozempic.com/how-to-take/ozempic-dosing.html?showisi=true&&utm_source=google&utm_medium=cpc&utm_term=ozempic%20max%20dose&utm_campaign=&mkwid=s-dc_pcrid_677045568674_pkw_ozempic%20max%20dose_pmt_e_slid__product_&pgrid=158457124030&ptaid=kwd-391252388809&gclid=CjwKCAjwkNOpBhBEEiwAb3MvvbD4RyT43KxnS_oVEd56ReoX247BiYR89-0cwaQSmS3XQHmjiIZ2KxoCNwgQAvD_BwE&gclsrc=aw.ds]