3 Weight Loss Injections for Sustainable Results

The global prevalence of obesity, a serious chronic disease, has reached alarming levels, with over 650 million adults living with obesity. Obesity is associated with an increased risk for over 200 other chronic diseases, including type 2 diabetes, heart disease, stroke, fatty liver disease, depression, sleep apnea, and some cancers.¹ In the United States, about 42% of all adults live with obesity, and two-thirds of adults meet the criteria for overweight (>25 kg/m2) or obesity (>30 kg/m2).^2,3

Because obesity is associated with significant morbidity and economic burden, there has been interest in developing medications to reduce the risk of cardiovascular and other chronic diseases related to obesity.⁴ As of 11/9/2023, there are now three FDA-approved medications for weight loss: Wegovy (semaglutide), Zepbound (tirzepatide), and Saxenda (liraglutide).

While lifestyle modifications, such as consuming a low-calorie diet and exercising, remain the foundation for effective weight loss, anti-obesity medications give hope to the many people struggling with managing their weight.

Liraglutide: Setting the Standard

Liraglutide is in a class of medications called glucagon-like peptide-1 (GLP-1) receptor agonists. Medications in this class act like your body’s naturally produced GLP-1 hormone. This hormone suppresses your appetite, increases satiety, and slows stomach emptying, so you feel full longer.

GLP-1 hormone also binds to receptors in the pancreas and stimulates insulin release. Insulin lowers glucose in the bloodstream by moving it into body cells, where it can be used for energy. Liraglutide treats diabetes and obesity.

Liraglutide: Clinical Trials

Liraglutide’s safety and efficacy were tested in the SCALE clinical trials. In the SCALE: Obesity and Prediabetes clinical trial, participants taking liraglutide lost about 7.4% of their body weight.

In the SCALE: Diabetes clinical trial, about 54% of the participants taking the 3.0 mg dose lost at least 5% of their body weight, and 25% lost at least 10%. About 40% of people taking liraglutide 1.8 mg and 21% taking a placebo lost at least 5% of their body weight.⁵

The SCALE: Maintenance clinical trial showed that people taking liraglutide, along with a reduced-calorie diet and exercise, could maintain or increase their weight loss while they continued to take liraglutide. ⁶

Summary: Average weight loss when taking liraglutide is 11 pounds with the 1.8 mg dose and 13–14 pounds with the 3.0 mg dose.

Semaglutide: A Game-Changer in Weight Loss

Like liraglutide, semaglutide is a GLP-1 receptor agonist. But its chemical composition means that it lasts longer in the body, so it can be taken once per week instead of daily.

Semaglutide slows stomach emptying so you feel full longer, increases insulin secretion from the pancreas to reduce abnormally high blood sugar, and signals your brain that you are satisfied and no longer hungry.

Semaglutide Clinical Trials

The Semaglutide Treatment Effect in People with Obesity (STEP) trials evaluated the weight loss efficacy of semaglutide in individuals with diabetes and obesity.

In STEP 1, a randomized, double-blind trial, individuals with overweight or obesity who took semaglutide, along with a reduced-calorie diet and exercise, lost an average of 14.9% of their body weight.⁷

In STEP-2, a randomized, double-blind trial, semaglutide 2.4 mg once weekly resulted in an average weight loss of 9.6% from baseline after 68 weeks of treatment. The study included adults with type 2 diabetes mellitus, overweight or obesity, and HbA1c (a measurement of blood sugar over three months) of 7%–10%.⁸

In STEP 3, participants took semaglutide and received intensive behavioral therapy. They lost an average of 16% of their body weight. These results were similar to the STEP 1 results.⁹

STEP 4 demonstrated whether people taking semaglutide would maintain their weight loss or continue to lose weight. The group that took semaglutide continued to lose weight. In contrast, the group that stopped semaglutide regained some of their lost weight. This trial illustrates the need to treat obesity as a chronic disease.¹⁰

Average weight loss when taking semaglutide is 14% to 16%.

Tirzepatide: A Dual Receptor Agonist for Weight Loss

Tirzepatide is a novel dual-receptor agonist that activates both the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. By targeting both pathways, tirzepatide offers a synergistic effect on weight loss and blood sugar control. Its once-weekly dosing schedule makes it a convenient option for patients seeking long-term weight management.

Tirzepatide reduces blood sugar levels, improves insulin sensitivity, improves blood lipid levels, curbs hunger, increases satiety, and helps you feel full longer.

Tirzepatide Clinical Trials

The SURPASS clinical trials evaluated tirzepatide’s safety and efficacy in treating type 2 diabetes. The SURMOUNT clinical trials evaluated its weight-loss potential.

In the SURPASS-1 study, which was double-blind and placebo-controlled, people who took 5 mg, 10 mg, or 15 mg of tirzepatide once a week lost more weight than people who took a placebo after 40 weeks of treatment. Participants taking the highest dose, tirzepatide 15 mg, achieved an average weight loss of 11% from baseline.¹¹

In SURPASS-2, tirzepatide 15 mg demonstrated a dose-dependent weight loss effect in participants with type 2 diabetes and obesity. The weight loss achieved with tirzepatide (15 mg) in SURPASS-2 was comparable to that of semaglutide (2.4 mg) in STEP-2.¹²

SURPASS-3 and 4 compared tirzepatide to insulin. Tirzepatide worked better than insulin in achieving glycemic control and weight loss.^13,14

SURMOUNT-1: Over 2,000 adults with overweight or obesity took 5, 10, or 15 mg of tirzepatide and lost 15%, 19%, or 21% of their body weight at 72 weeks, respectively, compared to those who took a placebo. ¹⁵

SURMOUNT-2: Similar weight loss of 12–15% was seen with tirzepatide 10 mg and 15 mg doses in participants with obesity and type 2 diabetes. ¹⁶

SURMOUNT-3: Additional weight loss of 21% occurred with tirzepatide 15 mg plus lifestyle intervention over 12 weeks for a total weight loss of 26.6% of body weight over a total of 84 weeks.¹⁷

Tirzepatide led to an average weight loss of 11% to 25%.

Comparing semaglutide, liraglutide and tirzepatide

Semaglutide and liraglutide are very similar medications, with the most obvious difference being their dosage frequency. Tirzepatide is a GLP-1 receptor agonist, like semaglutide and liraglutide, but it is also a GIP receptor agonist. Targeting two receptors leads to even greater weight loss.

Weight loss injectables: Benefits

All three weight-loss injectables are GLP-1 receptor agonists and, therefore, can have the following benefits:

• Stimulates insulin release
• Inhibits glucagon release
• Slows stomach emptying
• Suppresses appetite
• Increases satiety after eating
• Decreases abdominal fat
• Decreases blood pressure
• Reduces LDL (bad) cholesterol
• Increases HDL (good) cholesterol
• Decreases triglycerides
• Decreases blood sugar

Weight Loss Efficacy

Semaglutide and tirzepatide can be best compared using the STEP 2 trial and the SURPASS 1 and 2 trials. In all three trials, the individuals enrolled had both obesity and type 2 diabetes. Typically, weight loss in people with type 2 diabetes is less than in people without the condition.

Semaglutide and tirzepatide both showed significant weight-loss efficacy in clinical trials. In the STEP-2 trial, participants taking semaglutide 2.4 mg achieved an average weight loss of 9.6% from baseline after 68 weeks of treatment. In comparison, participants taking tirzepatide 15 mg in SURPASS-1 and SURPASS-2 achieved weight losses of 10.1% and 13.1% from baseline, respectively. The weight loss achieved with both drugs exceeded the weight loss observed with pre-existing weight-loss medications.¹⁸

Glycemic Control

Both semaglutide and tirzepatide demonstrated improvements in glycemic control. Semaglutide 2.4 mg in the STEP-2 trial resulted in a reduction in HbA1c levels by more than 1% compared to placebo. Tirzepatide 15 mg in SURPASS-1 and SURPASS-2 led to even greater decreases in HbA1c levels, surpassing the efficacy of semaglutide. However, it is important to note that hypoglycemic (low blood sugar) events were reported with both drugs, albeit at a low rate.¹⁸

Safety Profile

Both semaglutide and tirzepatide were generally well-tolerated in clinical trials, with gastrointestinal events being the most common adverse events reported. Nausea and diarrhea were the most frequently reported gastrointestinal events. The discontinuation rate due to adverse events was higher with both drugs compared to placebo.¹⁸

The most common side effects reported in weight loss drug clinical trials include:

• Nausea
• Diarrhea
• Vomiting
• Constipation
• Indigestion
• Stomach pain

Potential serious adverse effects associated with GLP-1 anti-obesity medications include:

• Diabetic retinopathy in people with type 2 diabetes
• Gallbladder disease
• Acute kidney injury
• Hypersensitivity or allergic reactions
• Thyroid cancer
• Injection site reactions
• Faster heart rate
• Low blood sugar
• Suicidal behavior or ideation
• Inflammation of the pancreas
• Intestinal blockage

All the GLP-1 drugs are fairly new, so this list may increase with increased drug use across populations.

Conclusion: What is the most effective weight loss injection?

Liraglutide, semaglutide, and tirzepatide are all three very effective prescription weight-loss medications. All three are FDA-approved anti-obesity medications that may also reduce the risk of cardiovascular disease.

All three medications can cause significant gastrointestinal side effects that improve over time. They are all expensive medications. They are not appropriate for all people, so it is essential to talk with a board-certified, licensed healthcare provider who has experience using these medications to learn more about the risk-versus-benefit profile of using these medications to treat obesity.

If you evaluate the medications in terms of their demonstrated weight-loss potential, then tirzepatide comes out as the winner.

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