Tirzepatide proves multiple benefits

In the Phase III SURPASS study program, the dual receptor agonist tirzepatide performed convincingly. The results of several post-hoc analyses are now also available. At the annual meeting of the European Association for the Study of Diabetes (EASD), an exploratory analysis based on SURPASS 1-5 and MRI data from SURPASS 3 were presented. On the one hand, there was a possible kidney-protective effect.
of tirzepatide and whether and how the muscle composition changes during the course of treatment.

In contrast to the GLP-1 receptor agonists (GLP-1-RA), which have been established for some time now, tirzepatide also binds to the GIP receptors. The SURPASS program includes studies investigating tirzepatide at doses of 5 mg, 10 mg and 15 mg as monotherapy, as an add-on to other treatments and in comparison with established blood glucose-lowering drugs in patients with type 2 diabetes. In the SURPASS 1-5 studies (Table 1), clinically relevant _HbA1c reductions were achieved at week 40 or 52 in all doses of tirzepatide, both when used alone and in combination treatment. Tirzepatide also proved to be superior to active comparators and placebo in terms of weight reduction [1–5]. Various post-hoc analyses investigated the extent to which the dual GIP/GLP-1 RA influences other clinically relevant parameters in type 2 diabetics.

Albuminuria is demonstrably reduced

Evaluations of the SURPASS 4 study indicate that tirzepatide has nephroprotective effects in type 2 diabetics at high cardiovascular risk [5]. To find out more about the specific effects of tirzepatide on the urine albumin-creatinine ratio (UACR), a post-hoc analysis of the SURPASS 1-5 studies was carried out [6]. It was found that tirzepatide treatment was associated with a clinically relevant reduction in UACR, indicating a renal protective effect. This was true for all type 2 diabetics studied, including those with reduced kidney function. Specifically, the researchers assessed the percentage difference in UACR for tirzepatide (5, 10, 15 mg) compared to the active comparator preparations. The analyses were conducted in the pooled total population of SURPASS 1-5 and in the populations pooled according to comparator products: Placebo (SURPASS 1 & 5); Semaglutide 1 mg (SURPASS 2); Insulin (SURPASS 3-4). The data were analyzed overall and for subgroups with a UACR value of ≥3.39 mg/mmol or an eGFR <60 ml/
min/1.73^m2 was evaluated. UACR data were available from a total of 6263 patients, of which 1846 had a UACR value of ≥3.39 mg/mmol and 537 had an eGFR <60 mL/min/1.73^m2. In all pooled SURPASS populations, the UACR decreased more with tirzepatide (at all doses) than in the comparison groups. The UACR reduction was most pronounced in subgroups with a baseline value of ≥3.39 mg/mmol or an eGFR <60 mL/min/1.73^m2.

No negative effects on the muscles

SURPASS 3 compared the efficacy and safety of tirzepatide versus titrated insulin degludec in over 1400 insulin-naïve adult type 2 diabetic patients whose glycemic control was inadequately controlled on metformin +/- SGLT-2 inhibitor for ≥3 months [4]. The average duration of diabetes in the study participants was 8.4 years. In a sub-study of SURPASS 3, MRI data were collected to determine the percentage of liver fat and the percentage of visceral and subcutaneous adipose tissue. In addition, an exploratory post-hoc analysis based on the MRI data collected addressed the question of how the weight loss achieved with tirzepatide affected the muscles [7,8]. The researchers calculated a prediction of the changes in muscle fat content and muscle volume based on data from the longitudinal study UK Biobank** (n=2942). This showed that in the SURPASS 3 MRI substudy (n=296), tirzepatide significantly reduced muscle fat content compared to insulin degludec. This effect was more pronounced than would have been expected based on ageing and weight loss during the study period. However, this did not apply to the same extent to muscle volume. In summary, it can be stated that the unavoidable decrease in muscle mass with weight-reducing medication was at least partially compensated for by a better composition of the muscle tissue, i.e. a lower fat content, during treatment with tirzepatide.

** The participants of the UK Biobank study (n=2942) were scanned at intervals of ~2.2 years, including MFI, FFMV or FFMV z-score.

In a subgroup analysis, it was also found that those with low muscle volume at baseline achieved comparable effects in terms of weight loss and muscle size compared to the other study participants taking tirzepatide [7].

Congress: EASD Annual Meeting

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HAUSARZT PRAXIS 2023; 18(11): 22–23