Dual GIP/GLP-1 receptor agonist as an innovative therapeutic option

The goals of individualized diabetes treatment today are not limited to achieving glycemic control, but many blood glucose-lowering drugs have clinically relevant additional benefits. Incretin-based therapies are particularly interesting for overweight type 2 diabetics, as they support weight reduction. In addition to the monoagonists, a dual GIP/GLP-1 receptor agonist, tirzepatide, is also currently available.

The glucagon-like peptide (GLP-1) and the glucose-dependent insulinotropic peptide (GIP) are hormones from the gastrointestinal tract that stimulate the release of insulin, among other things, and are also known as incretins. GLP-1 receptor agonists are incretin mimetics that stimulate the GLP-1 receptor and have been shown not only to lower blood sugar levels but also body weight. Moreover, an additional cardiovascular and renal benefit was shown for some representatives [1]. In the meantime, a dual GIP/GLP-1 receptor agonist has also been approved: Tirzepatide is a so-called Twinkretin, which can bind and activate both GIP receptors and GLP-1 receptors [2,3]. Tirzepatide achieves a GIP receptor affinity comparable to that of native GIP and binds the GLP-1 receptor with an affinity approximately five times weaker than native GLP-1 [4]. In addition to improving blood glucose levels, the SURPASS 1-5 studies showed that tirzepatide effectively reduced visceral adiposity, blood pressure, triglycerides, waist circumference, body weight and liver fat content. These improvements were seen across a wide range of patients, both as monotherapy in people with newly diagnosed type 2 diabetes and as combination therapy with metformin, SGLT-2 inhibitors and/or sulfonylureas or insulin. In Switzerland, tirzepatide is available under the trade name Mounjaro® [5].

Phase III study program SURPASS

The sample of subjects included in the SURPASS 1-5 studies represents a broad spectrum of patient characteristics and treatment situations in type 2 diabetes from [6–10]. Since different populations were recruited in this context, the baseline characteristics (e.g. duration of diabetes and mean _HbA1c value) varied between the individual studies (Table 1) .

Study duration: In SURPASS-1, -2 and -5 the study duration was 40 weeks and in SURPASS-3 52 weeks. This allowed a gradual titration over a period of up to 20 weeks to reach the 15 mg dose. The maintenance phase to assess therapeutic efficacy extended over a period of up to 32 weeks. In SURPASS-4, the primary endpoint was reached at 52 weeks after baseline, with some participants continuing treatment until week 104.

Comparison arms: In addition to placebo (SURPASS-1 and -5), semaglutide 1 mg (SURPASS-2), insulin degludec 100 U/ml (SURPASS-3) and insulin glargine 100 U/ml (SURPASS-4) were used in the comparison arms. Semaglutide is a GLP-1 receptor agonist.

Other: In addition to _HbA1c measurement, SURPASS-3 included a substudy on continuous glucose monitoring, in which 24-hour blood glucose profiles were analyzed, and a substudy in which the effects of treatment on liver fat content and other measures such as visceral fat were investigated using magnetic resonance imaging (MRI).

The most important results at a glance

The primary endpoint in SURPASS 1-5 was the change in _HbA1c at week 40 or 52 after baseline, with _baseline HbA1c between 7.94% and 8.52% (63-70 mmol/mol).

Tirzepatide led to a mean reduction in _HbA1c of -1.87% to -2.59% (-20 to -28 mmol/mol) compared to baseline values. These effects were dose-dependent and significantly more pronounced with tirzepatide 5, 10 and 15 mg compared to placebo (0.04%, SURPASS-1), semaglutide 1 mg (-1.86%, SURPASS-2), insulin degludec (-1.34%, SURPASS-3), insulin glargine 100 U/ml (-1.44%, SURPASS-4) or placebo with background insulin (-0.93%, SURPASS-5).

In each of the five studies, a significant proportion of participants treated with tirzepatide achieved an _HbA1c value of <7.0% (53 mmol/mol) (Fig. 1) or ≤6.5% (48 nmol/mol), which is in line with the recommendations of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [11,12]. An _HbA1c value <7% (53 mmol/mol) and ≤6.5% (48 mmol/mol) was achieved by 81-97% and 66-95% of participants respectively.

In the five SURPASS studies, the mean body weight at baseline was between 86 and 95 kg. Treatment with tirzepatide showed a clinically meaningful reduction in body weight and a significantly higher proportion achieved a targeted weight reduction of 5%, 10% and 15% compared to placebo and the active comparator arms.

Across SURPASS 1-5, the average weight loss in the three dose groups was 6.2-12.9 kg. The extent of weight reduction proved to be approximately proportional to the respective dose: 6.2-7.8 kg with tirzepatide 5 mg, 7.8-10.7 kg with the 10 mg dose and 9.5-12.9 kg with the 15 mg dose

All tirzepatide doses significantly reduced body weight compared to semaglutide 1 mg. The weight loss with tirzepatide 15 mg (-12.4 kg) was twice as high as with semaglutide 1 mg (-6.2 kg) [6]. A reduction in body weight was also observed when tirzepatide was combined with therapies associated with weight gain, such as insulin or sulfonylureas [9,10,12,13].

Up to 88% of participants receiving tirzepatide 15 mg achieved a weight loss of at least 5% from baseline at week 52, with an average weight at baseline of 94.3 kg and 32% treated with metformin plus an SGLT-2 inhibitor (range 77-88% for SURPASS 1-5) (Fig. 2) .

Among the participants who received tirzepatide 15 mg, a weight loss of at least 10% was achieved in up to 69% (range: 47-69%) and a weight loss of at least 15% in up to 43% (range: 27-43%).

In the participants treated with tirzepatide who used background insulin, 7-85% achieved a targeted reduction in body weight of at least 5%, 10% or 15% [10]. Weight loss with tirzepatide was evident as early as four weeks after treatment initiation (i.e. during the dose escalation phase) and continued until the primary study endpoints at week 40 or 52 after baseline, without reaching a plateau. In the SURPASS-4 study with a variable treatment duration of up to 104 weeks, weight loss reached a plateau at around one year and lasted up to 18 months or two years [9].

The safety profile of tirzepatide was generally similar to that of the GLP-1 receptor agonist class and the tirzepatide-associated safety results were consistent across SURPASS studies 1-5.

Mechanisms of action of tirzepatide

GLP-1 receptor agonists can improve glycemic control and reduce body weight in type 2 diabetes by enhancing glucose-stimulated insulin secretion, reducing food intake, inhibiting glucagon secretion in hyperglycemic or euglycemic states, and delaying gastric emptying [2]. GIP also increases glucose-stimulated insulin secretion in people without type 2 diabetes, while this effect is attenuated in people with type 2 diabetes, but unlike GLP-1, it stimulates glucagon secretion in hypoglycemic states [2]. In normal physiology, the two incretin hormones GIP and GLP-1 exert relatively short-lived effects at their respective receptors due to their rapid degradation by the enzyme dipeptidyl peptidase-4 and a resulting half-life of a few minutes [2].

Clinical studies have shown that the effects of tirzepatide on glycemic control are associated with improvements in β-cell function, insulin sensitivity and α-cell function [2,6]. Human studies suggest that weight loss is only partly responsible for the improvement in insulin sensitivity and that tirzepatide improves insulin sensitivity per unit weight more than a selective GLP-1 receptor agonist, with this effect being most pronounced in people with greater weight loss [2].

Literature:

1. “GIP/GLP-1 dual agonists: Turbo for successful diabetes therapy”, Prim. Univ. Prof. Dr. Thomas Stulnig, www.karl-landsteiner.at,(last accessed 03.04.2024)
2. De Block C, et al: Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective. Diabetes Obes Metab 2023; 25(1): 3-17.
3. Lean MEJ, et al: Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomized trial. Lancet Diabetes Endocrinol 2019; 7(5): 344-355.
4. Willard FS, et al: Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 2020; 5(17):e140532.
5. Swissmedic: Medicinal product information, www.swissmedicinfo.ch,(last accessed 03.04.2024)
6. Frías JP, et al: Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021; 385(6): 503-515.
7. 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.
8. Ludvik B, et al: Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomized, open-label, parallel-group, phase 3 trial. Lancet 2021; 398(10300): 583-598.
9. Del Prato S, et al: Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomized, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021; 398(10313): 1811-1824.
10. 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.
11. American Diabetes Association: Glycemic targets: standards of medical care in diabetes – 2021. Diabetes Care 2021; 44(Supplement 1): S73-S84.
12. Garber AJ, et al: Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary. Endocr Pract 2020; 26(1): 107-139.
13. American Diabetes Association: Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes – 2021. Diabetes Care. 2021;44(Supplement 1): S111-S124.

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