Tirzepatide - a dual GIP and GLP-1 (GLP1) receptor agonist

Glucagon-like peptide-1 (GLP-1) receptor agonists are an effective treatment option for patients with type 2 diabetes

• act by stimulating insulin secretion in hyperglycemic states, suppressing glucagon secretion in hyperglycemic or euglycemic states, delaying gastric emptying, decreasing appetite, and reducing body weight

Tirzepatide

• is a dual glucose-dependent insulinotropic polypeptide-GLP-1 receptor agonist
• structure is primarily based on the glucose-dependent insulinotropic polypeptide amino acid sequence and includes a C20 fatty diacid moiety
  • C20 fatty di-acid moiety that prolongs the duration of action, thus allowing once-weekly subcutaneous administration
• is a 39 amino acid synthetic peptide with agonist activity at both the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, with a greater affinity to GIP receptor
• GIP, unlike GLP-1, is glucagonotropic in a glucose-dependent manner
• the efficacy and safety of once-weekly tirzepatide was compared with semaglutide, a selective GLP-1 receptor agonist (1)
  • estimated mean change from baseline in the glycated haemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide
    
    
  • reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons)
    
    
  • most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhoea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide
    
    
  • It was concluded that in patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks
    
    
• tirzepatide for weight loss
  • in SURMOUNT-1
    • double-blind, randomized, controlled trial
    • assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period
      • baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher
      • mean percentage change in weight at week 72 was -15.0% (95% confidence interval [CI], -15.9 to -14.2) with 5-mg weekly doses of tirzepatide, -19.5% (95% CI, -20.4 to -18.5) with 10-mg doses, and -20.9% (95% CI, -21.8 to -19.9) with 15-mg doses and -3.1% (95% CI, -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo)
      • 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more
      • most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation
      • study authors concluded:
        • "..In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight.."
  • in SURMOUNT-2
    • 72-week trial in adults living with obesity and type 2 diabetes
      • once-weekly tirzepatide 10 mg and 15 mg provided substantial reduction in bodyweight (4)
        • mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12.8% and -14.7%, respectively, and -3.2% with placebo

In the UK, tirzepatide is now approved for use in adults with a BMI of 30kg/m² or more (obesity), as well as those with a BMI between 27-30kg/m² (overweight) who also have weight-related health problems such as prediabetes, high blood pressure, high cholesterol, or heart problems (5)

• is advised that obese or overweight female patients using oral contraceptives should consider using a barrier method of contraception or switching to a non-oral contraceptive method for 4 weeks after starting tirzepatide and for 4 weeks after each increase in dose as it may affect efficacy of the contraceptive pill
• starting dose is 2.5mg once a week for four weeks, increasing to 5mg once a week
• dose may then be increased in at least 4-week intervals up to the maximum dose of 15mg once weekly

A review noted (2):

• Tirzepatide is a novel incretin-based therapy for T2DM
  • showed robust HbA1c (-1.94%), FSG (-54.7 mg/dl), and body weight (-8.5 kg) reductions, without an increased risk of hypoglycaemia
  • at the highest dose (15 mg), tirzepatide reduced: HbA1c (-2.1%), FSG (-61.1 mg/dl), and body weight (-8.6 kg)

Weight change in comparison to continuation or cessation of tirzepatide treatment (6):

• after 36 weeks of open-label maximum tolerated dose of tirzepatide (10 or 15 mg), adults (n = 670) with obesity or overweight (without diabetes) experienced a mean weight reduction of 20.9%
• from randomization (at week 36), those switched to placebo experienced a 14% weight regain and those continuing tirzepatide experienced an additional 5.5% weight reduction during the 52-week double-blind period
• after achieving clinically meaningful weight reduction during a 36-week tirzepatide lead-in treatment period, adults with obesity or overweight who continued treatment with maximum tolerated dose tirzepatide for an additional 52 weeks demonstrated superior weight maintenance and continued weight reduction compared to those who switched to placebo

Reference:

1. Frias JP et al;SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021 Jun 25.
2. Bhagavathula AS, Vidyasagar K, Tesfaye W. Efficacy and Safety of Tirzepatide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Phase II/III Trials. Pharmaceuticals (Basel). 2021;14(10):991. Published 2021 Sep 28. doi:10.3390/ph14100991
3. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jun 4. doi: 10.1056/NEJMoa2206038. Epub ahead of print. PMID: 35658024
4. Garvey WT et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet June 26, 2023
5. MHRA (November 8th 2023). MHRA authorises diabetes drug Mounjaro (tirzepatide) for weight management and weight loss
6. Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. Published online December 11, 2023. doi:10.1001/jama.2023.2494