Clinical Overview: Tirzepatide for Type 2 Diabetes

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 trials.

Tirzepatide (Mounjaro) is a novel drug for the treatment of type 2 diabetes in addition to diet and exercise to improve glycemic control for 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 trials.2

Both GLP-1 and GIP are classified as incretins and are expressed throughout the body, including pancreatic beta cells and the gastrointestinal tract. 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 decrease in blood glucose levels. There are 2 incretins produced: GIP and GLP-1.

GLP-1 and GIP increase insulin from beta cells and glucose uptake by muscles and decrease blood glucose. GLP-1 stimulates glucose dependent decrease of glucagon from alpha cells, lowering glucose production from the liver and decreasing blood glucose.

GIP promotes the growth and survival of the pancreatic beta cell and stimulation of 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 decreased GLP-1 and GIP production.3

Tirzepatide’s protein sequence was based on the sequence of endogenous GIP and its pharmacological action on GLP-1 receptors is comparable to endogenous GIP. It is a 39 amino acid linear synthetic peptide conjugated to a C20 fatty diacid moiety.

The drug is also highly bound to albumin in the plasma, which prolongs its half-life.4 The long half-life of tirzepatide allows for a once-weekly dosing via subcutaneous administration. It is available in 6 doses: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg.1

The mechanisms of action for tirzepatide include stimulation of first- and second-phase insulin secretion, as well reduced glucagon levels, both in a glucose-dependent manner. The drug delays gastric emptying, lowers fasting and postprandial glucose concentration, decreases food intake, and reduces 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 dual agonism at GIP and GLP-1R. Studies have demonstrated that coadministration 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 trials, tirzepatide was compared to semaglutide (GLP-1), insulin glargine and insulin degludec. Participants in the SURPASS-2 program achieved better average hemoglobin A1C reductions with tirzepatide than 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 hypoglycemia.5 SURPASS-4 study evaluated patients with type 2 diabetes and elevated cardiovascular risk. Compared with glargine, tirzepatide demonstrated a greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk.6

SURPASS-5 investigated the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine among 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 ongoing on drugs that not only have a hypoglycemic effect, but also fight obesity and overweight. Antidiabetic drugs are gaining more interest among people who want to lose weight, also when excess body weight is not accompanied by diabetes, pre-diabetes, or insulin resistance.

In the recent study, the mean change in body weight was a key secondary endpoint and participants who were using tirzepatide lost between 12 lbs (5 mg) and 25 lbs (15 mg) on average. The study of people with diabetes who used tirzepatide found that they lost an average of 15% of their starting body weight.8

The weekly injections of tirzepatide were tested in more than 2500 nondiabetic people who had a body mass index (BMI) exceeding 30 or over BMI 27 and had at least 1 chronic condition related to 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 starting body weight in a 72-week, double-blind, randomized clinical trial. Participants administered placebo lost an average of 2.4 % to 3.1% of starting weight using 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 physical activity per week. Although it certainly helped to reduce weight, it doesn't explain the scale of the weight loss seen in the study.

The type of weight loss we see when people exercise and change their caloric intake ranges from 5% to 7%. This study showed significantly greater weight loss (the average 15% to 20.9% weight loss) while using tirzepatide.8

The most frequently reported adverse effects 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 include 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, therefore it has the potential to affect the absorption of concomitantly administered oral medications.1

References

  1. Mounjaro. Prescribing Information. Lilly USA, LLC.
  2. 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, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6.
  3. Coskun T, Sloop 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: 10.1016/j.molmet.2018.09.009.
  4. 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
  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. doi: 10.1016/S0140-6736(21)01443-4
  6. Del Prato S, Kahn SE, Pavo I, et al; for the SURPASS-4 Investigators. 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. doi: 10.1016/S0140-6736(21)02188-7
  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. doi:10.1001/jama.2022.007.
  8. 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.