While glucagon-like peptide (GLP)-1 receptor agonists have been successfully used in the treatment of diabetes for some time, there are now agents that activate not only the GLP-1 receptor but also the glucose-dependent insulinotropic polypeptide (GIP) receptor. Dual GLP-1/GIP agonists are considered promising new drugs for the treatment of obesity and type 2 diabetes.
Incretins such as glucagon-like peptide 1 (GLP-1) or gastric inhibitory peptide (GIP) are gut hormones that promote insulin release. The peptide hormone GIP is released from the duodenum into the blood after a meal. Together with GLP-1, GIP stimulates insulin secretion from pancreatic beta cells. In overweight type 2 diabetics with a body mass index (BMI) ≥28 kg/m2, the current treatment recommendations of the Swiss Society of Diabetology and Endocrinology (SGED) advise an early combination of metformin with GLP-1 receptor agonists (GLP-1-RA), as the latter have shown greater effects than SGLT-2 inhibitors (SGLT-2-i) in terms of weight reduction [1]. GLP-1 RAs with high potency with respect to weight loss include semaglutide or, at higher doses, liraglutide and dulaglutide [1]. In trials, semaglutide at a dose of 2.4 mg and the new GLP-1/GIP agonist tirzepatide have performed best in this regard to date. In Switzerland, tirzepatide has been approved for the treatment of adult type 2 diabetics since September 2022 [2].
First GLP-1/GIP agonist convinces in overweight people with and without diabetes
The SURPASS-1 trial evaluated the efficacy and safety of tirzepatide (5 mg /10 mg/15 mg) compared with placebo in adults with type 2 diabetes [3]. After 40 weeks of treatment, tirzepatide at all three doses resulted in above-average reductions in blood glucose and body weight compared with baseline values. Participants had a mean duration of diabetes of 4.7 years, a baseline HbA1c of 7.9%, and a baseline weight of 85.9 kg. Tirzepatide resulted in a reduction in HbA1c of 1.87% (5 mg), 1.89% (10 mg), and 2.07% (15 mg), respectively, whereas there was an increase of +0.04% in the placebo condition. There was also a dose-dependent effect with regard to weight reduction: -7.9% (5 mg) and -9.3% (10 mg) and -11.0% (15 mg), respectively. This corresponds to a significant superiority compared to placebo (-0.9%).
In the SURPASS-5 study, adults with inadequately controlled type 2 diabetes received tirzepatide as an adjunct to insulin glargine and metformin. Of the 475 randomized type 2 diabetic patients (44% female; mean age 60.6 years; mean HbA1c 8.31%), 451 underwent the entire study [4]. Inclusion criteria included baseline HbA1c of 7.0% to 10.5% (53-91 mmol/mol), BMI of min. 23 and therapy with stable doses of once-daily insulin glargine (>20 IU/d or >0.25 IU/kg/d) with or without metformin (≥1500 mg/d). In all tirzepatide doses (5 mg/10 mg/15 mg), a considerable weight reduction was achieved from baseline to week 40, whereas in contrast, a slight weight gain occurred in the placebo arm (Fig. 1, Fig. 2) . The dual GLP-1/GIP agonist was also convincing in terms of glycemic control. The mean change in HbA1c in the study arms with tirzepatide at the above doses was -2.11% and -2.40% and -2.34%, respectively. In the placebo condition, the corresponding value was -0.86%.
That tirzepatide is also effective in obese patients without diabetes is shown by data from the SURMOUNT-1 trial [5]. At baseline, mean body weight was 104.8 kg and mean BMI was 38.0. 94.5% of the participants had a BMI of min. 30 on. At week 72 after baseline, weight reduction of 15.0% (5 mg), 19.5% (10 mg), and 20.9% (15 mg), respectively, was achieved in the tirzepatide study arms, corresponding to significant superiority over placebo (p<0.001, all doses). A weight reduction of at least 5% achieved with tirzepatide 5 mg/10 mg/15 mg was 85% and 89% and 91% of study participants, respectively. In conclusion, GLP-1-RA and the GLP-1/GIP agonist tirzepatide have an important role in the treatment of obesity and diabetes.
Literature:
- Gastaldi G, et al: Recommendations of the Swiss Society of Endocrinology and Diabetology (SGED/SSED) for the Treatment of Type 2 Diabetes Mellitus, 2023, www.sgedssed.ch,(last accessed 06.06.2023).
- Drug Information, www.swissmedicinfo.ch,(last accessed 06.06.2023).
- 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.
- Dahl D, 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.
- Jastreboff AM; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022; 387(3): 205-216.
- “Goals and benefits of effective obesity management – 2023 update,” Professor Dror Dicker, MD, DGIM Congress 04/24/2023.
HAUSARZT PRAXIS 2023; 18(6): 28
