medwireNews: The publication of two SURPASS-3 substudies in The Lancet Diabetes & Endocrinology reveals significant benefits of tirzepatide on liver and abdominal fat in people with type 2 diabetes, as well as on time in target glucose range.
The SURPASS-3 trial tested the dual inhibitor of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 against insulin degludec in people whose type 2 diabetes was poorly controlled on metformin with or without a sodium-glucose cotransporter 2 inhibitor.
Participants taking any of the three tirzepatide doses (5, 10, or 15 mg/week) had significantly larger reductions in glycated hemoglobin than those taking degludec, and they lost weight rather than gaining it.
In the SURPASS-3 MRI substudy, 296 people underwent magnetic resonance imaging at baseline and at week 52. Average liver fat content was 15.7% at baseline, but during treatment this decreased by 6.35, 8.21, and 7.78 percentage points, on average, in people taking the 5, 10, and 15 mg tirzepatide doses. All of these changes were significant relative to the average 3.19 percentage point reduction in the degludec group.
In addition, visceral adipose tissue decreased from a baseline average of 6.55 L by an average of 1.10–1.65 L across the tirzepatide groups versus a 0.38 L increase in the degludec group, and abdominal subcutaneous adipose tissue decreased by 1.40–2.25 L versus a 0.63 L increase from a baseline average of 10.38 L.
Liver enzyme levels decreased significantly more with 10 and 15 mg tirzepatide than with degludec, report Ángel Rodríguez (Lilly Spain, Madrid) and study co-authors, and these changes correlated with the reduction in liver fat.
In a linked commentary, Giovanni Targher (University and Azienda Ospedaliera Universitaria Integrata of Verona, Italy) says: “It is reasonable to hypothesise that the observed beneficial effect of tirzepatide on [liver fat content] is an indirect effect of weight loss, reductions in insulin resistance, lipotoxicity, low-grade inflammation, and improved mitochondrial function.”
However, he highlights the absence of liver biopsies and non-invasive methods of assessing fibrosis, which could have revealed more about the treatment benefits.
The other substudy – SURPASS-3 CGM – looked at glycemic outcomes in 243 people who were assigned to wear a continuous glucose monitor for an average of 6 days at baseline, 24 weeks, and 52 weeks.
The primary outcome was time spent in a tight target range of 71–140 mg/dL (3.94–7.77 mmol/L), which at baseline was 23% and 22% in the pooled tirzepatide 10 and 15 mg groups and the degludec group, respectively.
By week 52, this had increased to a corresponding 73% and 48%, with the difference between the two being statistically significant, report Katelyn Brown (Lilly Corporate Center, Indianapolis, Indiana, USA) and co-researchers.
At this time, people in the tirzepatide groups were spending 91% of their time, on average, within the standard range of 71–180 mg/dL (3.94–10.0 mmol/L), due largely to an average 14% greater reduction in the time above range than was achieved with degludec.
The commentary accompanying this study is written by Natasha Malkani and Vanita Aroda, both from Brigham & Women’s Hospital in Boston, Massachusetts, USA, who describe the tight target range as “unique and provocative.”
They say the focus on this, “not only with preprandial values but throughout the day, raises the question of whether such stringent glycaemic objectives, essentially translating to normalisation of glycaemia, represent a practical approach that could translate to better outcomes compared with the current recommendations.”
The commentators highlight the potential for adverse effects with very tight glycemic control, as observed with older antihyperglycemic medications.
But they believe “it is plausible that near euglycaemia achieved by therapeutic approaches that restore underlying physiological processes could positively impact the course of disease and risk of diabetes-related complications, thus shifting our framework from thinking about glycemic targets to considering how glycaemia is safely and effectively restored.”
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