Dual GIP/GLP-1 agonist therapy demonstrated superior glucose control and weight loss in patients with diabetes compared to selective GLP-1 receptor agonists in preclinical and clinical studies.
Tirzepatide (Mounjaro) is a new drug for treating type 2 diabetes in addition to diet and exercise to improve glycemic control in adults.1 It is a glucagon-like peptide-1 (GLP-1) receptor agonist with added glucose-dependent insulinotropic polypeptide (GIP). Dual GIP/GLP-1 agonist therapy demonstrated better glucose control and weight loss compared to selective GLP-1 receptor agonists in preclinical and clinical studies.2
Both GLP-1 and GIP are classified as incretins and are expressed throughout the body, including pancreatic and gastrointestinal beta cells. These stimulate insulin secretion in a glucose-dependent manner.
Incretins are a group of metabolic hormones that are released from the enteroendocrine cells into the bloodstream after eating and stimulate a reduction in blood glucose levels. 2 incretins are produced: GIP and GLP-1.
GLP-1 and GIP increase beta-cell insulin and muscle glucose uptake, and lower blood glucose. GLP-1 stimulates the glucose-dependent decrease of glucagon from alpha cells, decreases hepatic glucose production and lowers blood glucose.
GIP promotes pancreatic beta cell growth and survival and stimulates adipogenesis. Dipeptidyl peptidase-4 (DPP-4) is a serine protease responsible for the inactivation of GLP-1 and GIP. In patients with type 2 diabetes, there is a decreased production of GLP-1 and GIP.3
The protein sequence of tirzepatide was based on the sequence of endogenous GIP and its pharmacological action on GLP-1 receptors is similar to that of endogenous GIP. It is a linear synthetic peptide of 39 amino acids, conjugated to a C20 fatty acid group.
The drug is also highly bound to plasma albumin, which extends its half-life.4 The long half-life of tirzepatide allows for weekly dosing via subcutaneous administration. It is available in 6 doses: 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg.1
The mechanisms of action of tirzepatide include stimulation of first and second phase insulin secretion, as well as decreased glucagon levels, both in a glucose-dependent manner. The drug delays gastric emptying, lowers fasting and postprandial glucose concentration, reduces food intake, and decreases body weight in patients with type 2 diabetes. In addition, tirzepatide increases insulin sensitivity.
The glycemic and weight control effects of this drug are believed to arise from double agonism at GIP and GLP-1R. Studies have shown that co-administration of a GIP and GLP-1R agonist significantly increases insulin response and suppresses glucagon secretion compared to separate administration of either hormone alone.2
In clinical studies, tirzepatide was compared with semaglutide (GLP-1), insulin glargine and insulin degludec. Participants in the SURPASS-2 program achieved better mean hemoglobin A1C reductions with tirzepatide than with semaglutide.4
In the SURPASS-3 program, tirzepatide was superior to titrated insulin degludec, with greater reductions in HbA1c and body weight at week 52 and a lower risk of hypoglycaemia.5 The SURPASS-4 study evaluated patients with type 2 diabetes and an increased cardiovascular risk. Compared to glargine, tirzepatide showed a greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Treatment with tirzepatide was not associated with an increased cardiovascular risk.6
SURPASS-5 investigated the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine in patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine. The study found that participants had statistically significant improvements in glycemic control after 40 weeks when the tirzepatide was added to the insulin glargine.7
Research is being conducted into drugs that not only have a hypoglycemic effect, but also fight obesity and overweight. Antidiabetics are becoming increasingly popular among people who want to lose weight, even if overweight is not associated with diabetes, prediabetes or insulin resistance.
In the recent study, mean change in body weight was an important secondary endpoint, and participants taking tirzepatide lost between 12 lbs (5 mg) and 25 lbs (15 mg) on average. The study of people with diabetes who took tirzepatide found that they lost an average of 15% of their original body weight.8
The weekly injections of tirzepatide were tested in more than 2,500 non-diabetic people with a body mass index (BMI) greater than 30 or greater than BMI 27 and who had at least one chronic condition associated with being overweight, such as high blood pressure, high cholesterol or cardiovascular disease.8
The study confirmed that people without diabetes lost an average of 15% to 20.9% of their starting weight in a 72-week, double-blind, randomized clinical trial. Participants who received placebo lost an average of 2.4% to 3.1% of starting weight with the same advice and recommendations as the first group.8
Study participants also received support to help them maintain a healthy diet with a daily deficit of 500 calories, as well as at least 150 minutes of exercise per week. While it certainly helped reduce weight, it doesn’t explain the magnitude of weight loss seen in the study.
The type of weight loss we see when people exercise and change their calorie intake ranges from 5% to 7%. This study showed significantly more weight loss (average weight loss of 15% to 20.9%) while taking tirzepatide.8
The most frequently reported adverse reactions after tirzepatide were nausea, diarrhea and constipation. Because the drug is a GLP-1 agonist, it has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.
The Boxed Warning includes thyroid C cell tumors. Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Tirzepatide delays gastric emptying and therefore may affect the absorption of concomitantly administered oral medications.1
- mounjaro. Prescribing Information. Lilly USA, LLC.
- Rosenstock, J, 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, randomized phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.116/S0140-6736(21)01324-6.
- Coskun T, Sloep KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018 Dec;18:3-14. doi: 10.116/j.molmet.2018.09.009.
- Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385(6)(suppl):503-515. doi: 10.1056/NEJMoa2107519
- Ludvik B, Giorgino F, Jódar E, et al. Tirzepatide once weekly versus once daily insulin degludec as adjunct to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomized, open-label, phase 3 study with parallel groups. Lancet. 2021;398(10300):583-598. doi: 10.116/S0140-6736(21)01443-4
- Del Prato S, Kahn SE, Pavo I, et al; for the SURPASS-4 researchers. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomized, open-label, multicenter, phase 3 parallel group study. Lancet. 2021;398(10313):1811-1824. doi: 10.116/S0140-6736(21)02188-7
- Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide versus 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. doi:10.1001/jama.2022.007.
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. doi:10.1056/NEJMoa2206038.