What is the comparison of weight loss among three generations of Incretin (INCRETIN)-based therapies, including Glucagon-like peptide-1 (GLP-1) receptor agonists?

From the Guidelines

Incretin-based therapies for weight loss have evolved across three generations, with the newest third-generation dual GIP/GLP-1 receptor agonist tirzepatide demonstrating the most impressive results, with weight loss of up to 20.9% over 72 weeks, as shown in the SURMOUNT-1 trial 1.

Comparison of Weight Loss Across Generations

The three generations of incretin-based therapies offer progressively better weight reduction outcomes.

• First-generation DPP-4 inhibitors are weight-neutral or produce minimal weight loss of 1-2 kg.
• Second-generation GLP-1 receptor agonists, such as semaglutide and liraglutide, show more significant results, with semaglutide achieving 10-15% body weight reduction over 68 weeks at doses of 2.4 mg weekly, as demonstrated in the STEP trials 1.
• The newest third-generation dual GIP/GLP-1 receptor agonist tirzepatide demonstrates the most impressive results, with weight loss of up to 20.9% over 72 weeks, as shown in the SURMOUNT-1 trial 1.

Mechanism of Action and Lifestyle Modifications

These medications work by reducing appetite, increasing satiety, slowing gastric emptying, and improving insulin sensitivity.

• For optimal results, they should be used alongside lifestyle modifications including caloric restriction and increased physical activity.
• Doses are typically titrated up gradually to minimize gastrointestinal side effects like nausea, vomiting, and diarrhea.

Clinical Evidence and Recommendations

The clinical evidence supports the use of GLP-1 receptor agonists, such as semaglutide, for weight loss in adults with obesity, as recommended in the AGA clinical practice guideline on pharmacological interventions for adults with obesity 1.

• The SELECT trial showed a significant reduction in the incidence of cardiovascular death, MI, or stroke in patients with pre-existing CVD who were overweight or obese, but without diabetes, treated with weekly subcutaneous semaglutide 1.
• The use of tirzepatide, a dual GIP/GLP-1 receptor agonist, is recommended for adults with obesity or overweight with weight-related complications, due to its impressive weight loss results and potential cardiovascular benefits, as demonstrated in the SURMOUNT-1 trial 1.

From the FDA Drug Label

Body Weight (kg) Baseline (mean) 84.5 87.0 86.2 85.5 Change at Week 40b-1.0 -6.3 -7.0 -7. 8 Difference from placebob (95% CI) -- -5.3c (-6.8, -3.9) -6.0c (-7.4, -4.6) -6.8c (-8.3, -5.4)

Body Weight (kg) Baseline (mean) 93.7 92.5 94.8 93.8 Change at Week 40b-5.7 -7.6 -9.3 -11.2 Difference from semaglutideb (95% CI) -- -1.9c (-2.8, -1.0) -3.6d (-4.5, -2.7) -5.5d (-6.4, -4. 6)

Body Weight (kg) (Mean) Baseline91.892.792.4 Change from baselineb-1.4-2.3-2.2

Body Weight (kg) (Mean) Baseline85.586.585.8 Change from baselineb-2.7-3.1-1. 5 Difference from sitagliptinb (95% CI)-1.2 (-1.8, -0.6)-1.5 (-2.1, -0.9)-

The weight loss associated with tirzepatide was:

• -6.3 kg, -7.0 kg, and -7.8 kg at week 40 for the 5 mg, 10 mg, and 15 mg doses, respectively, compared to placebo.
• -7.6 kg, -9.3 kg, and -11.2 kg at week 40 for the 5 mg, 10 mg, and 15 mg doses, respectively, compared to semaglutide. The weight loss associated with dulaglutide was:
• -1.4 kg, -2.3 kg, and -2.2 kg at week 26 for the 0.75 mg and 1.5 mg doses, respectively.
• -2.7 kg and -3.1 kg at week 52 for the 0.75 mg and 1.5 mg doses, respectively, compared to sitagliptin. It is not possible to directly compare the weight loss of the three generations of incretin-based therapy, as the provided data is from different studies with different patient populations and study designs. 2 3

From the Research

Comparison of Weight Loss of 3 Generations of Incretin-Based Therapy

• The weight loss effects of different generations of incretin-based therapy have been studied in various clinical trials 4, 5, 6, 7, 8.
• A study comparing semaglutide 2.0 mg and 1.0 mg found that the higher dose resulted in greater weight loss, with a mean change in bodyweight of -6.9 kg compared to -6.0 kg with the lower dose 4.
• Another study compared tirzepatide with semaglutide and found that tirzepatide resulted in greater weight loss, with least-squares mean estimated treatment differences of -1.9 kg, -3.6 kg, and -5.5 kg for the 5 mg, 10 mg, and 15 mg doses of tirzepatide, respectively, compared to semaglutide 7.
• A review of real-world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer GLP-1RA-based weight-loss therapies found that the observed weight reduction in clinical practice tends to be lower than in randomized controlled trials, but outcomes approach those seen in trials when focusing on highly adherent patients 6.
• Oral semaglutide has also been shown to be effective in reducing body weight, with significant reductions in HbA1c and body weight compared to placebo when added to insulin therapy 8.

Key Findings

• Semaglutide 2.0 mg results in greater weight loss compared to semaglutide 1.0 mg 4.
• Tirzepatide results in greater weight loss compared to semaglutide 7.
• Oral semaglutide is effective in reducing body weight when added to insulin therapy 8.
• Real-world evidence suggests that the observed weight reduction with GLP-1RA-based weight-loss therapies tends to be lower than in randomized controlled trials, but outcomes approach those seen in trials when focusing on highly adherent patients 6.

Weight Loss Comparison

• Semaglutide 2.0 mg: -6.9 kg 4
• Semaglutide 1.0 mg: -6.0 kg 4
• Tirzepatide 5 mg: -1.9 kg (compared to semaglutide) 7
• Tirzepatide 10 mg: -3.6 kg (compared to semaglutide) 7
• Tirzepatide 15 mg: -5.5 kg (compared to semaglutide) 7
• Oral semaglutide: significant reductions in HbA1c and body weight compared to placebo when added to insulin therapy 8