The MRI (magnetic resonance imaging) sub-study achieved its primary and secondary endpoints. As evaluated by MRI scans, the sub-study showed all three doses of tirzepatide (5 mg, 10 mg, 15 mg) led to greater reductions in liver fat content compared to insulin degludec and reductions in volume of visceral adipose tissue and abdominal subcutaneous adipose tissue compared to increases in volume of both measurements with insulin degludec at 52 weeks.
“Increased ectopic fat – such as liver fat or visceral adipose tissue – is commonly seen in adults with type 2 diabetes and is associated with an inflammatory response and increased cardiometabolic risk,” said Amalia Gastaldelli, Ph.D., Research Director of Cardiometabolic Risk Unit,
Tirzepatide is a novel investigational once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single molecule, representing a new class of medicines being studied for the treatment of type 2 diabetes.
SURPASS-3 was a 52-week, multi-center, randomized, phase 3, open-label trial evaluating the efficacy and safety of tirzepatide compared to titrated insulin degludeci in adults with type 2 diabetes who have inadequate glycemic control on stable doses of metformin with or without an SGLT-2 inhibitor. Study participants were insulin-naïve and had a mean duration of diabetes of 8.4 years, a baseline A1C of 8.17 percent and a baseline weight of 94.3 kg.
The SURPASS-3 MRI sub-study compared the effect of tirzepatide to titrated insulin degludec on liver fat content (LFC), volume of visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) in 296 participants as evaluated by MRI scans at baseline and at 52 weeks. The subpopulation of adults with type 2 diabetes who participated in this sub-study had an overall baseline LFC of 15.7 percent.
Results among participants taking tirzepatide at 52 weeks showed:
- Greater absolute reduction from baseline in LFC for pooled 10 mg and 15 mg arms (-8.09% from 15.67% at baseline) compared to insulin degludec (-3.38% from 16.58% at baseline), the primary endpoint.
- Greater relative reduction from baseline in LFC (29.78%-47.11% across the three doses) compared to 11.17% for insulin degludec.
- The majority of participants taking tirzepatide achieved at least a 30% reduction in LFC from baseline (66.9%-81.4% across the three doses) compared to a third of those taking insulin degludec (32.12%).
- Up to -1.65 liter (L) reduction from baseline of 6.81 L in VAT (15 mg) and -2.25 L reduction from baseline of 10.21 L in ASAT (10 mg) compared to an increase with insulin degludec (+0.38 L from 6.34 L baseline and +0.63 L from 10.04 L baseline respectively).
The overall safety profile of tirzepatide in SURPASS-3 was similar to the well-established GLP-1 receptor agonist class. Gastrointestinal side effects were the most commonly reported adverse events and decreased with continued dosing.
“In this study, we found that more than twice as many participants taking tirzepatide experienced greater than 30 percent reduction in liver fat content compared to those taking insulin degludec,” said Laura Fernández Landó, M.D., senior medical director,
Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for blood glucose management in adults with type 2 diabetes and for chronic weight management. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF).
About the SURPASS-3 sub-studies and the SURPASS clinical trial program
The SURPASS-3 MRI sub-study compared the effect of tirzepatide to titrated insulin degludec on liver fat content (LFC), volume of visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) as evaluated by MRI scans in a subpopulation of SURPASS-3 trial participants. The subpopulation were adults with type 2 diabetes that had a higher risk of elevated LFC as measured by having a Fatty Liver Index ≥60. A total of 296 participants were enrolled in this sub-study and randomized to receive either tirzepatide doses of 5 mg, 10 mg or 15 mg or insulin degludec. The primary objective was to compare the effect of tirzepatide (pooled 10 mg and 15 mg) on change from baseline in the percentage of LFC compared to insulin degludec as measured by MRI scans at baseline and at 52 weeks. The secondary objectives included comparing tirzepatide 5 mg, 10 mg and 15 mg versus insulin degludec in the proportion of participants achieving LFC ≤10%; the proportion of participants with a relative decrease from baseline in LFC ≥30%; the volume of abdominal visceral and subcutaneous adipose tissue and the change from baseline.
The SURPASS phase 3 global clinical development program for tirzepatide has enrolled more than 20,000 people with type 2 diabetes across 10 clinical trials, five of which are global registration studies. The program began in late 2018, and all five global registration trials have been completed.
An estimated 463 million adults worldwide2 have diabetes. Type 2 diabetes is the most common type, accounting for an estimated 90 to 95 percent of all diabetes cases3. Diabetes is a chronic disease that occurs when the body does not properly produce or use the hormone insulin.
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about tirzepatide as a potential treatment for people with type 2 diabetes and the timeline for future readouts, presentations and other milestones relating to tirzepatide and its clinical trials and reflects
1 Cusi, K. The effects of tirzepatide on liver fat content and abdominal adipose tissue in patients with type 2 diabetes (SURPASS-3 MRI). Session S42a. Presented virtually at the 57th
2 Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020.
3 International Diabetes Federation. IDF Diabetes Atlas, 9th edn.
i The mean starting dose of insulin degludec was 10 units per day. The insulin dose was titrated following a treat-to-target algorithm with the goal of fasting blood glucose below 90 mg/dL.
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