SURMOUNT-MMO

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 Myocardial Infarction (MI), Nonfatal Stroke, Coronary Revascularization, or Heart Failure Events) Follow-up: Up to 5 Years

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 :

Time to Onset of Type 2 Diabetes (T2D)
Hierarchical Composite of Renal Death or End-Stage Renal Disease (ESRD), Sustained Decline in Estimated Glomerular Filtration Rate (eGFR), and eGFR Slope

Inclusion Criteria:

Have a body mass index (BMI) ≥27.0 kilogram/square meter (kg/m ²)
Are either
- individuals ≥40 years of age with established cardiovascular disease (CVD).
  - CVD is defined as meeting at least one of the following:
    - Coronary artery disease, s/p AMI, PCI/stent, CABG
    - Cerebrovascular disease
  - Peripheral arterial disease OR
  - individuals without established CVD but have the presence of cardiovascular (CV) risk factors (primary prevention)
    - women 55-69 or men 50-64 years old with at least 3 risk factors like CKD, tobacco use, dyslipidemia, hypertension at screening, prediabetes, hs-CRP>2 Lp(a) >100 nmol/L CAC >400
    - women ≥70 or men, ≥65 years old with at least 2 risk factors at screening.

Exclusion Criteria:

Have diabetes (T1D) or (T2D),
Have laboratory evidence diagnostic of diabetes mellitus at screening of HbA1c ≥6.5%
Any one of the following CV conditions within 90 days prior to screening
- MI
- acute coronary syndrome
- stroke
- coronary or peripheral arterial revascularization procedure, which may also include carotid artery revascularization, or
- acute decompensated heart failure
Have a known clinically significant gastric emptying abnormality such as severe gastroparesis or gastric outlet obstruction or have undergone or currently planning any gastric bypass (metabolic) surgery or restrictive bariatric surgery. Note: Liposuction or abdominoplasty are not considered as gastric bypass procedures.
Have a history of chronic or acute pancreatitis
Have a family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.
Have acute or chronic hepatitis, or clinical signs or symptoms of any other liver disease, or have elevated liver enzyme measurements,
Have a presence or history of malignant neoplasms within the past 5 years prior to screening.

Tirzepatide: A new challenger for type 2 diabetes management?

Author: John Wilding

https://diabetes.medicinematters.com/type-2-diabetes/gip-glp-1-agonists/tirzepatide-john-wilding/18481648

Are two incretins better than one?

· 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.

‘Mind the GIP’

· 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.

The story so far with tirzepatide

· 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