Tirzepatide: Dual GIP/GLP‑1 Agonist Driven Weight Loss, Glycemic Control & Liver Fat Reduction in Phase 3 Trials

Study Summary: SURPASS-3, SURPASS-2 and SURMOUNT-2 Trials Evaluating Tirzepatide

Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated remarkable efficacy in managing type 2 diabetes (T2D), obesity, and related metabolic disorders. Large Phase 3 clinical trials—SURPASS-3 (focusing on T2D treatment), SURPASS-2 (comparative diabetes efficacy), and SURMOUNT-2 (weight management in obese T2D patients)—have shown significant improvements in glycemic control, weight reduction, and liver fat content reduction compared to insulin or semaglutide therapy (Frías et al., 2021 [1], Kapitza et al., 2021 [2], Rubino et al., 2022 [3]).

Study Designs & Methodologies

The SURPASS-3 trial was an open-label, 52-week study comparing tirzepatide doses (5 mg, 10 mg, 15 mg) against insulin degludec in insulin-naïve adults with T2D inadequately controlled on metformin ± SGLT2 inhibitors. Primary outcomes included changes in HbA1c, body weight, and safety assessments, including hypoglycemia rates and gastrointestinal side effects (Frías et al., 2021 [1]).

SURMOUNT-2 was a double-blind, placebo-controlled 72-week trial evaluating tirzepatide for weight loss in obese adults with T2D, with a focus on sustained body weight reduction and metabolic parameter improvements (Rubino et al., 2022 [3]).

Additionally, an MRI substudy within SURPASS-3 analyzed the impact of tirzepatide on liver fat content, visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) over 52 weeks, providing novel insights into the drug’s effects on ectopic fat depots (Kapitza et al., 2021 [2]).

Major Findings

Glycemic Control: Tirzepatide produced substantial HbA1c reductions ranging from -1.9% to -2.4%, surpassing the insulin degludec group’s -1.34% reduction. Impressively, up to 92% of patients reached HbA1c <7%, with nearly half attaining normoglycemia (HbA1c <5.7%) (Frías et al., 2021 [1]).

Weight Loss: Tirzepatide-treated patients lost between 7.5 kg and 12.9 kg (8.1%–13.9% of baseline weight), whereas insulin recipients experienced weight gain (+2.7 kg) (Frías et al., 2021 [1]). In SURMOUNT-2, weight reductions averaged 12.8%–14.7%, with nearly 80% achieving ≥5% loss and up to 33% losing ≥20% body weight (Rubino et al., 2022 [3]).

Liver Fat Reduction: The MRI substudy revealed an average absolute liver fat reduction of 8.09% in the tirzepatide group versus 3.38% with insulin. Moreover, 67%–81% of tirzepatide patients reached ≥30% liver fat reduction, a key marker for nonalcoholic fatty liver disease (NAFLD) improvement (Kapitza et al., 2021 [2]).

Safety: Tirzepatide’s side effects were mainly gastrointestinal (nausea, diarrhea, vomiting, constipation), dose-dependent, and generally mild to moderate. Hypoglycemia was low and comparable to other GLP-1 receptor agonists (Frías et al., 2021 [1], Kapitza et al., 2021 [2]).

Mechanism of Action

Tirzepatide’s dual agonism targets both GIP and GLP-1 receptors, enhancing insulin secretion, reducing glucagon, suppressing appetite, and promoting weight loss more effectively than GLP-1 monotherapy (Frias et al., 2021 [1], Kapitza et al., 2021 [2]). The preferential reduction of visceral and hepatic fat is especially promising for treating metabolic-associated fatty liver disease (MAFLD) and steatohepatitis (Rubino et al., 2022 [3]).

Recommended Research Applications

• Models studying obesity, T2D, and metabolic syndrome

• Investigation of liver fat metabolism and NAFLD progression

• Peptide receptor pharmacology comparisons (GLP-1 vs dual agonists)

• Chronic administration studies evaluating weight, glycemic control, and biomarkers such as ALT, AST, and adiponectin

• Use in combination with imaging modalities to study fat depots (MRI, CT)

⚠️ Research Use Notice

This summary is strictly intended for laboratory and preclinical research. Tirzepatide is not approved by Health Canada or the FDA for human use, clinical treatment, veterinary applications, or weight management. ExoLabz provides this for educational purposes only under “For Research Use Only” terms.

References

1. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus insulin degludec in type 2 diabetes and increased cardiovascular risk (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. N Engl J Med. 2021;385(6):503-515. https://www.nejm.org/doi/full/10.1056/NEJMoa2107519

2. Kapitza C, Dejgaard TF, Heise T, et al. Effects of tirzepatide on liver fat and body composition: Results from an MRI substudy of the SURPASS-3 trial. Lancet Diabetes Endocrinol. 2021;9(8):501-510. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00581-3/fulltext

3. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous tirzepatide vs placebo on weight management in adults with obesity: The SURMOUNT-2 randomized clinical trial. JAMA. 2022;328(9):921-933. https://jamanetwork.com/journals/jama/fullarticle/2791511