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Tirzepatide: worth the weight

Prepared by: Ana Safri, PharmD PGY2 Ambulatory Care Resident, Boston Medical Center
Reviewed by: Katelyn O'Brien, PharmD, BCPS, CDCES, BC-ADM and Courtney Cameron, PharmD 

What is tirzepatide?

Tirzepatide (Mounjaro) is the first in its class peptide that activates both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Both GIP and GLP-1 are incretin hormones released in response to nutrient uptake in the gut, however GIP is responsible for ~2/3 of the total effect, allowing a synergistic effect with tirzepatide’s mechanism. Similar to other GLP-1, GIP stimulates insulin secretion in hyperglycemic states. However, unlike GLP-1, GIP only suppresses glucagon secretion in hyperglycemic states, leading to potentially lower risk of hypoglycemia.

Tirzepatide is a single dose pen with a no see needle and has a half-life of approximately 5 days, allowing for once weekly administration. The recommended starting dose is 2.5mg which is to reduce gastrointestinal side effects and no glycemic effects. The dose can be increased in 2.5mg increments every 4 weeks as needed for glycemic control, with a maximum dose of 15mg.

Tirzepatide has demonstrated unprecedented efficacy for A1c lowering and weight loss in clinical trials and was approved by the FDA in May 2022 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.¹ Although it has not yet been approved for obesity, tirzepatide has been incorporated in the 2023 ADA guidelines and categorized as very high efficacy for weight loss.² The FDA has granted tirzepatide fast track review to be designated as a treatment for obesity.

Summary of SURPASS trials

Although the SURPASS trials evaluated A1c reduction as the primary endpoint, weight reduction was studied as a secondary endpoint. All doses of tirzepatide showed superior reduction from baseline in A1c and body weight. Table 1 provides a summary of the SURPASS trials.

Table 1: Summary of SURPASS trials

Effect on weight loss

Currently the weight loss observed with semaglutide is greater than that reported for other approved anti-obesity medications. One critique of the SURPASS II trial is that tirzepatide was not compared to the full 2.4mg dose of semaglutide (Wegovy) approved for weight loss.⁴ However, this was a diabetes trial and not a weight loss trial and at the time of the study, the maximum approved dose of semaglutide for diabetes was 1mg. The maximum dose of semaglutide for diabetes has since been increased to 2mg. 

Although no head to head trials comparing tirzepatide to semaglutide 2mg exists, an adjusted indirect treatment comparison study aimed to compare these two agents based on the results from SURPASS 2 and SUSTAIN FORTE.⁸ This indirect analysis was possible due to the common comparator arm of semaglutide 1mg in both trials. Both trials implemented similar inclusion and exclusion criteria and had similar baseline populations. The more restrictive and overlapping criteria from both trials were used in the analysis. The analysis concluded that both tirzeptide 10mg and 15mg doses reduced body weight from baseline significantly more than semaglutide 2mg with an ETD of -3.15kg (p <0.001) and -5.15kg (p <0.001) at week 40, respectively (Figure 1). No significant difference between the tirzepatide 5mg and semaglutide 2mg doses was found. 

Figure 1: Change in bodyweight with tirzepatide 5mg, 10mg, and 15mg versus semaglutide 2mg⁸

The SURMOUNT I trial aimed to evaluate tirzepatide for the treatment of obesity in adults without diabetes.⁹ This was a 72-week double blind, randomized, placebo-controlled phase 3 trial comparing tirzepatide 5mg, 10mg, and 15mg to placebo. The co-primary endpoints were percentage change in body weight from baseline and weight reduction of at least 5% at week 72. All three tirzepatide doses were found to be superior to placebo for both outcomes (Figure 2). At week 72, more patients receiving tirzepatide had reductions in body weight of at least 10%, 15%, 20%, and 25% from baseline compared to those receiving placebo (P<0.001).

Figure 2: Percentage change in body weight with tirzepatide 5mg, 10mg, and 15mg versus placebo ⁹                

Although, no trial compares tirzepatide to semaglutide at the target dose approved for weight loss, inferences can be drawn by comparing the results of the SURMOUNT I trial and the STEP I trial. The STEP I trial compared semaglutide 2.4mg to placebo for weight reduction in patients without diabetes.¹⁰ The inclusion criteria was identical for both trials and baseline characteristics for body weight, BMI, and waist circumference were very similar across all participants. Based on these results, tirzeaptide 5mg seems to perform similarly to semaglutide 2.4mg, whereas tirzepatide 10mg and 15mg doses seem to produce greater weight loss than semaglutide 2.4mg (Figure 3).

Figure 3: Left (SURMOUNT I): weight reduction of 5%, 10%, 15%, 20%, and 25% or more at week 72 with tirzepatide 5mg, 10mg, and 15mg versus placebo.⁹ Right (STEP I): weight reduction of 5%, 10%, 15%, and 20% or more at week 68 with semaglutide 2.4mg versus placebo.¹⁰

Summary:

• Tirzepatide activates both GIP and GLP-1 receptors, acting synergistically to respond to nutrient uptake in the blood and reduce blood glucose.
• Tirzepatide was approved by the FDA for A1c lowering in Type 2 Diabetes in May 2022
• Although it has not yet been approved for obesity, tirzepatide demonstrated significant weight reduction when analyzed as the secondary outcome in the SURPASS trials and as the primary outcome in the SURMOUNT I trial.
• There is no direct comparison analysis between tirzepatide and semaglutide at doses approved for weight loss, however inferences of tirzepatide’s superior efficacy can be drawn from side by side comparisons of similarly designed trials
• Place in therapy, as included in the ADA 2023 Standards of Care, is in patients with T2DM who have a compelling need to reduce weight and achieve A1c lowering.¹¹

Impact on PharmD/CDCES:

• Pharmacists/CDCES can help identify patients that would most benefit from tirzepatide’s A1c lowering and weight reducing effects
• Pharmacists/CDCES can provide appropriate patient counseling regarding tirzepatide’s administration, benefits, adverse drug reactions, and storage
• Pharmacists/CDCES can assist other healthcare providers to safely transition patients from a GLP-1 RA to tirzepatide
• Pharmacists can facilitate insurance/cost barriers for eligible patients based on approved indications

 References:

1. Type 2 diabetes treatment to lower A1C: Mounjaro™(tirzepatide).Mounjaro. https://www.mounjaro.com/
2. ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Supplement_1):S140-S157.
3. Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2021 Jul 17;398(10296):212]. Lancet. 2021;398(10295):143-155.
4. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515.
5. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598.
6. Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824.
7. Dahl D, Onishi Y, Norwood P, et al. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA. 2022;327(6):534-545.
8. Vadher K, Patel H, Mody R, et al. Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2 mg in patients with type 2 diabetes: An adjusted indirect treatment comparison. Diabetes Obes Metab. 2022;24(9):1861-1868.
9. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216.
10. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002.
11. Diabetes Care2023;46(Supplement_1):S140–S157