A Study of Tirzepatide on th Reductiono on Morbidity and Mortality in Adults with Obesity (SURMOUNT-MMO)
A Phase 3, Randomized, Double-blind, Placebo-Controlled Study to Investigate the Effect of Tirzepatide on the Reduction of Morbidity and Mortality in Adults With Obesity
Participants will receive escalated doses of tirzepatide subcutaneously (SC) up to a maximum tolerated dose vs placebo randomized in a 1:1 fashion.
Primary Outcome Measures :
Time to first occurrence of any component event of composite, all-cause death, nonfatal MI, nonfatal stroke, coronary revascularization, or heart failure events that results in hospitalization or urgent visits.
Secondary Outcome Measures :
Author: John Wilding
· The normal regulation of post-prandial glucose metabolism is dependent on the incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP), which are secreted by the intestinal L‑cells and K‑cells, respectively. These hormones both enhance glucose-dependent insulin secretion and are part of normal post-meal satiety signaling. GIP may also play a role in fat metabolism in adipose tissue.
· In people with type 2 diabetes, there appears to be a reduction in secretion of GLP‑1 and responses to GIP are diminished, which may contribute to hyperglycemia. Long-acting GLP‑1 receptor agonists, such as exenatide, liraglutide, dulaglutide, and semaglutide, were developed on the basis of experimental studies with GLP‑1 infusions which showed that it helps to lower glucose in type 2 diabetes. Interest in GIP agonists has been limited, however, as it was thought that GIP is relatively ineffective at lowering glucose in type 2 diabetes.
· Recent research has challenged previously held views on GIP, with suggestions that, in the presence of higher GLP‑1 levels, GIP sensitivity can be restored in type 2 diabetes. There is also new experimental evidence to suggest that GIP, like GLP‑1, may help lower bodyweight in animal models of obesity, and could have favorable effects on lipid metabolism and liver fat, due to direct effects on adipocytes that promote lipid clearance. Hence, although GIP may be ineffective when given alone, a combination with GLP‑1 (with the right balance) may prove to be an even more effective treatment for diabetes than current GLP‑1 analogs. It has also been suggested that the combination may be useful for treatment of obesity and fatty liver disease.
· One of the first of the dual GIP/GLP-1 agonists developed, tirzepatide, is currently undergoing phase 3 clinical trials.
· Tirzepatide can be considered an imbalanced and biased (more active against GIP receptor) dual GLP-1/GIP agonist. A phase 2 trial looked at four doses of tirzepatide (given subcutaneously, once weekly for 26 weeks) compared with placebo and the GLP‑1 analog dulaglutide. In this trial, the highest dose used (15 mg) resulted in a glycated hemoglobin (HbA1c) reduction of 1.89%, compared with 1.26% for dulaglutide. Weight loss was 11.3 kg compared with 2.7 kg for dulaglutide. Adverse effects of tirzepatide were similar to dulaglutide, with gastrointestinal side effects being most prominent.
· Of interest, an analysis from the same trial showed reductions in triglycerides that were greater than were seen with dulaglutide treatment (a 37% fall at the highest dose), and also reductions in the atherogenic lipoproteins APO-CIII and APO-B. Statistical analysis suggested these improvements were independent of the greater weight loss seen with tirzepatide. It is therefore interesting to speculate whether this may translate into a greater effect on cardiovascular disease in an outcome trial